JBJS | Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Articular Cartilage. Part II: Degeneration and Osteoarthrosis, Repair, Regeneration, and Transplantation*†

The Journal of Bone & Joint Surgery, Volume 79, Issue 4

Instructional Course Lecture | April 01, 1997

Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Articular Cartilage. Part II: Degeneration and Osteoarthrosis, Repair, Regeneration, and Transplantation*†

J. A. BUCKWALTER, M.D.‡, IOWA CITY, IOWA; H. J. MANKIN, M.D.§, BOSTON, MASSACHUSETTS

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An Instructional Course Lecture, The American Academy of Orthopaedic Surgeons

The Journal of Bone & Joint Surgery. 1997; 79:612-32

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Introduction

Joint pain and loss of mobility are among the most common causes of impairment in middle-aged and older people^36,134. In many instances, the degeneration of articular cartilage and alterations in other joint tissues that result from the loss of structure and function of articular cartilage cause the pain and the loss of motion^{28,46,47,85,118,150}. This occurs most frequently in the clinical syndrome of idiopathic or primary osteoarthrosis, but it may also result from joint injury or from developmental, metabolic, and inflammatory disorders that destroy the articular surface, causing secondary osteoarthrosis^28,46,118. An understanding of the degeneration of articular cartilage, osteoarthrosis, and the potential for restoring an articular surface depends to a large extent on an appreciation of the biological behavior and the responsiveness of articular cartilage to injury and disease. Of considerable importance is the observation, first reported centuries ago and confirmed by multiple investigators over the last fifty years, that adult articular cartilage does not have the capacity to repair structural damage resulting from injury or disease^29,32,71. This observation has contributed to the view that adult articular cartilage is an inert bearing surface, like high-density polyethylene or metal, and that degeneration of the articular surface with age is the result of mechanical wear with inevitable, irreversible loss of structure and mechanical performance resulting from joint use⁶². The implication of this view is that, other than limiting joint use or loading, little or nothing can be done to prevent the degeneration of articular cartilage, and the most appropriate treatment for advanced degeneration of cartilage leading to the clinical syndrome of osteoarthrosis is replacement of the articular surface. Alternatively, if articular cartilage is not inert, in particular if it has the capacity to restore and remodel itself, then mechanical wear from joint use may not cause degeneration and osteoarthrosis, and therapeutic approaches aimed at maintaining or restoring articular cartilage are appropriate for at least some patients. A determination of which view is correct is critical for developing and implementing methods of preventing and treating osteoarthrosis.

This review covers the current understanding of the degeneration of articular cartilage (the alterations in composition and the deterioration in structure that lead to the loss of function of articular cartilage), the relationship between the degeneration of articular cartilage and osteoarthrosis as well as that between degeneration of articular cartilage and joint use, and approaches to restoring the composition, structure, and function of articular cartilage.

*Printed with permission of The American Academy of Orthopaedic Surgeons. This article will appear in Instructional Course Lectures, Volume 47, The American Academy of Orthopaedic Surgeons, Rosemont, Illinois, March 1998.

†No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were the National Institutes of Health and the Veterans Administration.

‡Department of Orthopaedics, University of Iowa College of Medicine, 01013 Pappajohn Pavilion, Iowa City, Iowa 52242. E-mail address: joseph-buckwalter@uiowa.edu.

§Orthopaedic Service, Gray 606, Massachusetts General Hospital, Boston, Massachusetts 02114.

‡Department of Orthopaedics, University of Iowa College of Medicine, 01013 Pappajohn Pavilion, Iowa City, Iowa 52242. E-mail address: joseph-buckwalter@uiowa.edu.

§Orthopaedic Service, Gray 606, Massachusetts General Hospital, Boston, Massachusetts 02114.

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TABLE I KNOWN CAUSES OF JOINT DEGENERATION (SECONDARY OSTEOARTHROSIS)

Cause	Presumed Mechanism
Intra-articular fracture	Damage to articular cartilage or incongruity of joint, or both

High-intensity-impact joint-loading	Damage to articular cartilage or subchondral bone, or both

Ligament injuries	Instability of joint

Dysplasia of joint and cartilage (developmental and hereditary)	Abnormal shape of joint or abnormal articular cartilage, or both

Aseptic necrosis	Bone necrosis leads to collapse of articular surface and incongruity of joint

Acromegaly	Overgrowth of articular cartilage produces incongruity of joint or abnormal cartilage, or both

Paget disease	Distortion or incongruity of joint due to bone-remodeling

Ehlers-Danlos syndrome	Instability of joint

Gaucher disease (hereditary deficiency of enzyme glucocerebrosidase, leading to accumulation of glucocerebroside)	Bone necrosis or pathological fracture leads to incongruity of joint

Stickler syndrome (progressive, hereditary arthro-ophthalmopathy)	Abnormal development of joint or articular cartilage, or both

Infection of joint (inflammation)	Destruction of articular cartilage

Hemophilia	Multiple joint hemorrhages

Hemochromatosis (excess deposition of iron in multiple tissues)	Mechanism unknown

Ochronosis (hereditary deficiency of enzyme homogentisic acid oxidase leading to accumulation of homogentisic acid)	Deposition of homogentisic acid polymers in articular cartilage

Calcium pyrophosphate deposition disease	Accumulation of calcium pyrophosphate crystals in articular cartilage

Neuropathic arthropathy (Charcot joints due to syphilis, diabetes mellitus, syringomyelia, myelomeningocele, leprosy, congenital insensitivity to pain, amyloidosis)	Loss of proprioception and joint sensation results in increased impact loading and torsion, instability of joint, and intra-articular fracture

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TABLE I KNOWN CAUSES OF JOINT DEGENERATION (SECONDARY OSTEOARTHROSIS)

Cause	Presumed Mechanism
Intra-articular fracture	Damage to articular cartilage or incongruity of joint, or both

High-intensity-impact joint-loading	Damage to articular cartilage or subchondral bone, or both

Ligament injuries	Instability of joint

Dysplasia of joint and cartilage (developmental and hereditary)	Abnormal shape of joint or abnormal articular cartilage, or both

Aseptic necrosis	Bone necrosis leads to collapse of articular surface and incongruity of joint

Acromegaly	Overgrowth of articular cartilage produces incongruity of joint or abnormal cartilage, or both

Paget disease	Distortion or incongruity of joint due to bone-remodeling

Ehlers-Danlos syndrome	Instability of joint

Gaucher disease (hereditary deficiency of enzyme glucocerebrosidase, leading to accumulation of glucocerebroside)	Bone necrosis or pathological fracture leads to incongruity of joint

Stickler syndrome (progressive, hereditary arthro-ophthalmopathy)	Abnormal development of joint or articular cartilage, or both

Infection of joint (inflammation)	Destruction of articular cartilage

Hemophilia	Multiple joint hemorrhages

Hemochromatosis (excess deposition of iron in multiple tissues)	Mechanism unknown

Ochronosis (hereditary deficiency of enzyme homogentisic acid oxidase leading to accumulation of homogentisic acid)	Deposition of homogentisic acid polymers in articular cartilage

Calcium pyrophosphate deposition disease	Accumulation of calcium pyrophosphate crystals in articular cartilage

Neuropathic arthropathy (Charcot joints due to syphilis, diabetes mellitus, syringomyelia, myelomeningocele, leprosy, congenital insensitivity to pain, amyloidosis)	Loss of proprioception and joint sensation results in increased impact loading and torsion, instability of joint, and intra-articular fracture

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TABLE II DIFFERENCES BETWEEN CHANGES IN ARTICULAR CARTILAGE DUE TO AGING AND THOSE DUE TO DEGENERATION IN OSTEOARTHROSIS^26,104

	Aging	Osteoarthrosis
Structure	Stable, localized, superficial fibrillation	Progressive, superficial fibrillation; fibrillation and fragmentation extending to subchondral bone; loss of tissue (decreased thickness of cartilage with complete loss in some regions); formation of fibro-cartilaginous repair tissue

Cells	Decreased density of chondrocytes with skeletal growth, alteration in synthetic activity (smaller, more variable aggrecans), decreased response to growth factors, decreased synthetic activity	Initial increase in synthetic and proliferative activity, loss of chondrocytes, eventual decreased synthetic activity, increased degradative enzyme activity, appearance of fibroblast-like cells in regions of fibro-cartilaginous repair tissue

Matrix	Decreased concentration of water, loss of large proteoglycan aggregates (decreased stability of aggregates), increased concentration of decorin, accumulation of degraded molecules (aggrecan and link protein fragments), increased collagen cross-linking, increased diameter of and variability in collagen fibrils, decreased tensile strength and stiffness in superficial layers	Initial increase in water content and, in some instances, in concentration of proteoglycans; disruption of collagenous macromolecular organization; progressive degradation and loss of proteoglycans, hyaluronan, and collagens; increased concentration of fibronectin; increased permeability and loss of tensile and compressive stiffness and strength

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TABLE II DIFFERENCES BETWEEN CHANGES IN ARTICULAR CARTILAGE DUE TO AGING AND THOSE DUE TO DEGENERATION IN OSTEOARTHROSIS^26,104

	Aging	Osteoarthrosis
Structure	Stable, localized, superficial fibrillation	Progressive, superficial fibrillation; fibrillation and fragmentation extending to subchondral bone; loss of tissue (decreased thickness of cartilage with complete loss in some regions); formation of fibro-cartilaginous repair tissue

Cells	Decreased density of chondrocytes with skeletal growth, alteration in synthetic activity (smaller, more variable aggrecans), decreased response to growth factors, decreased synthetic activity	Initial increase in synthetic and proliferative activity, loss of chondrocytes, eventual decreased synthetic activity, increased degradative enzyme activity, appearance of fibroblast-like cells in regions of fibro-cartilaginous repair tissue

Matrix	Decreased concentration of water, loss of large proteoglycan aggregates (decreased stability of aggregates), increased concentration of decorin, accumulation of degraded molecules (aggrecan and link protein fragments), increased collagen cross-linking, increased diameter of and variability in collagen fibrils, decreased tensile strength and stiffness in superficial layers	Initial increase in water content and, in some instances, in concentration of proteoglycans; disruption of collagenous macromolecular organization; progressive degradation and loss of proteoglycans, hyaluronan, and collagens; increased concentration of fibronectin; increased permeability and loss of tensile and compressive stiffness and strength

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TABLE III STAGES IN THE DEVELOPMENT AND PROGRESSION OF DEGENERATION OF ARTICULAR CARTILAGE IN OSTEOARTHROSIS^95-97,102

Stage	Description
I: Disruption or alteration of cartilage matrix	Disruption or alteration of macromolecular framework of matrix associated with increase in concentration of water that may be caused by mechanical insults, degradation of matrix macromolecules, or alterations of chondrocyte metabolism. At first, concentration of type-II collagen remains unchanged, but collagen meshwork may be damaged, and concentration of aggrecans and degree of proteoglycan aggregation decrease.

II: Response of chondrocytes to disruption or alteration of matrix	When chondrocytes detect a disruption or alteration of their matrix, they can respond by increasing synthesis and degradation of the matrix and by proliferating. Their response may restore tissue, maintain tissue in an altered state, or increase volume of cartilage. They may sustain an increased level of activity for years.

III: Decline in response of chondrocytes	Failure of chondrocytic response to restore or maintain tissue leads to loss of articular cartilage accompanied or preceded by decline in chondrocytic response. The causes for this decline remain poorly understood, but they may partially result from mechanical damage to tissue with injury to chondrocytes and down-regulation of chondrocytic response to anabolic cytokines.

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TABLE III STAGES IN THE DEVELOPMENT AND PROGRESSION OF DEGENERATION OF ARTICULAR CARTILAGE IN OSTEOARTHROSIS^95-97,102

Stage	Description
I: Disruption or alteration of cartilage matrix	Disruption or alteration of macromolecular framework of matrix associated with increase in concentration of water that may be caused by mechanical insults, degradation of matrix macromolecules, or alterations of chondrocyte metabolism. At first, concentration of type-II collagen remains unchanged, but collagen meshwork may be damaged, and concentration of aggrecans and degree of proteoglycan aggregation decrease.

II: Response of chondrocytes to disruption or alteration of matrix	When chondrocytes detect a disruption or alteration of their matrix, they can respond by increasing synthesis and degradation of the matrix and by proliferating. Their response may restore tissue, maintain tissue in an altered state, or increase volume of cartilage. They may sustain an increased level of activity for years.

III: Decline in response of chondrocytes	Failure of chondrocytic response to restore or maintain tissue leads to loss of articular cartilage accompanied or preceded by decline in chondrocytic response. The causes for this decline remain poorly understood, but they may partially result from mechanical damage to tissue with injury to chondrocytes and down-regulation of chondrocytic response to anabolic cytokines.

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TABLE IV SELECTED CLINICAL REPORTS OF METHODS OF RESTORING AN ARTICULAR SURFACE

Authors	No. of Patients, Joints, or Defects	Results	Comments
Excision of damaged cartilage and underlying bone (spongialization)
Fical et al.⁵⁵	85 patients (patellae)	67 (79%) good or excellent	Used for treatment of patellar chondral lesions

Joint débridement and penetration of subchondral bone
Ewing⁵¹	223 knees	163 (73%) improved	Increased severity of joint disease decreased probability of good result
Friedman et al.⁵⁹	73 knees	44 (60%) improved, 25 (34%) unchanged, 4 (5%) worse	Patients <40 yrs. old had better results
Johnson^81,82	>400 knees	75% satisfactory	12% of patients were symptom-free at 2 yrs.
Sprague¹⁵⁴	69 knees	51 (74%) good, 7 (10%) fair, 11 (16%) poor
Levy et al.⁸⁷	15 knees	6 excellent, 9 good, 0 fair or poor	All patients were competitive soccer players who had isolated chondral defects

Perichondrial grafts
Seradge et al.¹⁵¹	16 metacarpophalangeal joints	3 of 3 patients =20 yrs. old, 3 of 4 21—30 yrs. old, and 3 of 6 >30 yrs. old had good result	No patient >40 yrs. old had good result
	20 prox. interphalangeal joints	4 of 5 patients =20 yrs. old, 4 of 6 21—30 yrs. old, and 1 of 3 >30 yrs. old had good result
Homminga et al.⁷⁰	25 patients (30 defects [knees])	Mean score on knee-function scale improved; 28 (93%) defects filled with cartilaginous tissue	Biopsy showed hyaline tissue; results not related to age

Distraction of joint
van Valburg et al.¹⁵⁹	11 patients (11 ankles)	At average of 20 mos., all patients had less pain and 5 were pain-free; 3 of 6 patients who had radiographs had increased joint space	No patient had arthrodesis

Osteotomy
Weisl¹⁶⁴	757 hips	Joint space increased immediately in approx. 1/3 of patients and after 18 mos. in another 1/3; approx. 2/3 had relief of pain for 5 yrs.; after 10 yrs., only approx. 1/4 had relief	Better results in patients with increased joint space and in those <70 yrs. old who had unilateral disease
Reigstad and Grønmark¹⁴²	103 hips	70% had good result at 1 yr.; 51%, at 5 yrs.; and 30%, at 10 yrs.
Bergenudd et al.⁹	19 patients (knees)	Formation of new fibrocartilaginous surface in 9 patients, no change in 8, and deterioration of articular surface in 2	No correlation among histological findings, radiographic appearance, postop. varus-valgus angle, or clinical results
Insall et al.⁷⁵	95 knees	97% had good or excellent result at 2 yrs. and 85%, at 5 yrs.; 15% were pain-free at 9 yrs.

Carbon-fiber matrix
Muckle and Minns¹¹⁹	47 patients (knees)	36 (77%) had satisfactory result at average of 3 yrs.	No synovitis
Brittberg et al.¹⁶	36 patients (knees)	30 (83%) had good or excellent result at average of 4 yrs.	Good relief of pain, no adverse effects

Autologous chondrocyte transplantation
Brittberg et al.¹⁸	23 patients (knees)	14 of 16 patients who had femoral defect and 2 of 7 who had patellar defect had good or excellent result	Locking of joint eliminated, swelling and pain reduced
Buckwalter²³	66 patients (knees)	47 (71%) improved

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TABLE IV SELECTED CLINICAL REPORTS OF METHODS OF RESTORING AN ARTICULAR SURFACE

Authors	No. of Patients, Joints, or Defects	Results	Comments
Excision of damaged cartilage and underlying bone (spongialization)
Fical et al.⁵⁵	85 patients (patellae)	67 (79%) good or excellent	Used for treatment of patellar chondral lesions

Joint débridement and penetration of subchondral bone
Ewing⁵¹	223 knees	163 (73%) improved	Increased severity of joint disease decreased probability of good result
Friedman et al.⁵⁹	73 knees	44 (60%) improved, 25 (34%) unchanged, 4 (5%) worse	Patients <40 yrs. old had better results
Johnson^81,82	>400 knees	75% satisfactory	12% of patients were symptom-free at 2 yrs.
Sprague¹⁵⁴	69 knees	51 (74%) good, 7 (10%) fair, 11 (16%) poor
Levy et al.⁸⁷	15 knees	6 excellent, 9 good, 0 fair or poor	All patients were competitive soccer players who had isolated chondral defects

Perichondrial grafts
Seradge et al.¹⁵¹	16 metacarpophalangeal joints	3 of 3 patients =20 yrs. old, 3 of 4 21—30 yrs. old, and 3 of 6 >30 yrs. old had good result	No patient >40 yrs. old had good result
	20 prox. interphalangeal joints	4 of 5 patients =20 yrs. old, 4 of 6 21—30 yrs. old, and 1 of 3 >30 yrs. old had good result
Homminga et al.⁷⁰	25 patients (30 defects [knees])	Mean score on knee-function scale improved; 28 (93%) defects filled with cartilaginous tissue	Biopsy showed hyaline tissue; results not related to age

Distraction of joint
van Valburg et al.¹⁵⁹	11 patients (11 ankles)	At average of 20 mos., all patients had less pain and 5 were pain-free; 3 of 6 patients who had radiographs had increased joint space	No patient had arthrodesis

Osteotomy
Weisl¹⁶⁴	757 hips	Joint space increased immediately in approx. 1/3 of patients and after 18 mos. in another 1/3; approx. 2/3 had relief of pain for 5 yrs.; after 10 yrs., only approx. 1/4 had relief	Better results in patients with increased joint space and in those <70 yrs. old who had unilateral disease
Reigstad and Grønmark¹⁴²	103 hips	70% had good result at 1 yr.; 51%, at 5 yrs.; and 30%, at 10 yrs.
Bergenudd et al.⁹	19 patients (knees)	Formation of new fibrocartilaginous surface in 9 patients, no change in 8, and deterioration of articular surface in 2	No correlation among histological findings, radiographic appearance, postop. varus-valgus angle, or clinical results
Insall et al.⁷⁵	95 knees	97% had good or excellent result at 2 yrs. and 85%, at 5 yrs.; 15% were pain-free at 9 yrs.

Carbon-fiber matrix
Muckle and Minns¹¹⁹	47 patients (knees)	36 (77%) had satisfactory result at average of 3 yrs.	No synovitis
Brittberg et al.¹⁶	36 patients (knees)	30 (83%) had good or excellent result at average of 4 yrs.	Good relief of pain, no adverse effects

Autologous chondrocyte transplantation
Brittberg et al.¹⁸	23 patients (knees)	14 of 16 patients who had femoral defect and 2 of 7 who had patellar defect had good or excellent result	Locking of joint eliminated, swelling and pain reduced
Buckwalter²³	66 patients (knees)	47 (71%) improved

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Figs. 1-A, 1-B, and 1-C: Light micrographs of articular cartilage from rabbit patellae. The specimen was stained with safranin O to demonstrate the presence of glycosaminoglycans. Fig. 1-A: Normal articular cartilage. The matrix has a homogeneous, hyaline appearance. The matrix of the transitional and deep zones is stained diffusely with safranin O (dark regions), indicating a high concentration of glycosaminoglycans.

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Fig. 1-B Well formed repair cartilage six months after the creation of an osteochondral defect. Compared with the normal articular cartilage, the zonal organization is less well defined, the matrix has a fibrous appearance, and safranin-O staining is concentrated near a few cells. The zone of calcified cartilage has re-formed.

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Fig. 1-C Fibrillated repair cartilage one year after the creation of an osteochondral defect. Only a thin layer of fragmented tissue covers the subchondral bone, and the matrix lacks staining with safranin O.

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Fig. 2 Light micrographs showing the variability in osteochondral repair four to six weeks after the creation of four-millimeter-diameter, three-millimeter-deep osteochondral defects in the medial femoral condyle of a rabbit. A and B: Osteochondral repair restored a fibrocartilaginous articular surface that nearly reaches the level of the adjacent cartilage surface (magnification x 20). The arrowhead in B indicates the right edge of the defect. C: Osteochondral repair failed to restore an articular surface (magnification x 20). D: Higher-magnification view from the lower portion of the repair tissue shown in C (magnification x 35). The arrowheads indicate cartilaginous repair tissue. (Micrographs provided by Dr. A. I. Caplan, Department of Biology, Case Western Reserve University, Cleveland, Ohio^162,163.)

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Fig. 3 Light micrographs made after the treatment of experimental osteochondral defects in rabbits with use of cell transplants. These micrographs are in contrast with those in Fig. 2, showing untreated osteochondral defects. A: Osteochondral defect six months after transplantation of allogenic articular chondrocytes (magnification x 20). The arrowheads indicate the edges of the defect, which is filled with hyaline-like cartilage. B: Osteochondral defect six months after transplantation of autologous mesenchymal stem cells (magnification x 30). C and D: Higher magnification of osteochondral defect six months after transplantation of autologous mesenchymal stem cells (magnification x 100) (C is a polarized light image of D). The arrowheads mark the edge of the original defect, with repair tissue on the right and normal articular cartilage on the left. (Micrographs provided by Dr. I. A. Caplan, Department of Biology, Case Western Reserve University, Cleveland, Ohio^162,163.)

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Fig. 4 Light micrographs made four weeks after creation of experimental chondral defects in rabbits (A through D) and minipigs (E and F). A and B: Untreated defects that have not healed. In B, the arrowheads indicate mesenchymal cells and the arrows indicate proliferating chondrocytes. C: Treatment with chondroitinase AC led to the removal of some of the matrix proteoglycans, thereby improving the adhesion of repair cells to the cartilage surface (arrowheads). D: Treatment with chondroitinase AC and the mitogenic factor interleukin growth factor-1 stimulated the formation of layers of mesenchymal cells and a fibrous matrix (arrowheads). E: Treatment with a fibrin matrix and the chemotactic-mitogenic factor transforming growth factor-ß caused the defect to fill with mesenchymal tissue (s). F: The presence of layers of migrating mesenchymal cells (arrowheads) over normal cartilage suggests that these cells are chemotactically attracted to the defect from the synovial tissues. (Micrographs provided by E. Hunziker, University of Bern, Bern, Switzerland⁷³.)

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Fig. 5 Light micrographs showing chondral defects in the knee joints of minipigs. Top: untreated defect (D) in the articular surface. Bottom: new repair cartilage (R, edges marked by arrowheads) that formed in a chondral defect six weeks after treatment with free transforming growth factor-ß and liposome-encapsulated transforming growth factor-ß in a fibrin matrix. S, T, R, and CC = zones of articular cartilage (S = superficial, T = transitional, R = radial, and CC = calcified cartilage). (Micrographs provided by E. Hunziker, University of Bern, Bern, Switzerland⁷².)

Degeneration of Articular Cartilage and Osteoarthrosis

The degeneration, or the progressive loss of normal structure and function, of articular cartilage is an integral part of the clinical syndrome of osteoarthrosis. Osteoarthrosis, also referred to as degenerative joint disease, degenerative osteoarthritis, osteoarthritis, and hypertrophic osteoarthritis, consists of a generally progressive loss of articular cartilage accompanied by attempted repair of the cartilage, remodeling and sclerosis of subchondral bone, and, in many instances, the formation of subchondral bone cysts and marginal osteophytes^{28,47,54,85,118,123,133,143,150}. In addition to changes in the synovial joint, a diagnosis of osteoarthrosis requires the presence of symptoms and signs that may include joint pain, restriction of motion, crepitus with motion, joint effusions, and deformity. Osteoarthrosis occurs most frequently in the foot, knee, hip, spine, and hand joints¹³⁴, but it can cause deterioration of any synovial joint. The suffix itis, used in the terms degenerative arthritis, osteoarthritis, and hypertrophic arthritis, implies that osteoarthrosis is an inflammatory disease: evidence of synovitis is frequently present, but inflammation is not a major component. Therefore, the term osteoarthrosis more accurately reflects the current understanding of the pathogenesis of the disorder.

Osteoarthrosis develops most commonly in the absence of a known cause (primary or idiopathic osteoarthrosis). Less frequently, it develops as a result of a joint injury, infection, or one of a variety of hereditary, developmental, metabolic, and neurological disorders; this group of conditions is referred to as secondary osteoarthrosis (Table I). The age of onset associated with secondary osteoarthrosis depends on the underlying cause; thus, it may develop in young adults and even children as well as the elderly. In contrast, there is a strong association between the prevalence of primary osteoarthrosis and increasing age. Efforts to determine the exact prevalence of osteoarthrosis have important limitations, including difficulty in defining and establishing the diagnosis and in evaluating more than a few synovial joints in each individual; however, studies of the percentage of people who have osteoarthrosis as diagnosed on the basis of a medical history, examination, or radiographic evaluation uniformly confirm a striking increase in the prevalence of osteoarthrosis of the hand, foot, knee, and hip joints with increasing age^{28,86,118,131,134}. Studies of these joints have shown that the percentage of people who have mild, moderate, or severe radiographic changes indicative of osteoarthrosis in at least one joint increases progressively, from less than 5 per cent of people younger than twenty-five years old to more than 80 per cent of people more than seventy-five years old, and the percentage of people who have moderate or severe radiographic changes indicative of osteoarthrosis in at least one joint increases progressively, from less than 5 per cent of people younger than forty-five years old to more than 40 per cent of people more than seventy-five years old¹³⁴. Despite this strong association between age and osteoarthrosis, and despite the widespread view⁶² that osteoarthrosis results from "normal wear and tear" and "eventually stiffens the joints of virtually everybody who lives past 65," the relationships between joint use, aging, and joint degeneration remain uncertain. Furthermore, the changes observed in articular cartilage from older individuals differ from those observed in articular cartilage from people who have osteoarthrosis¹⁰⁴ (Table II), and normal lifelong joint use has not been shown to cause degeneration^26,30. Thus, osteoarthrosis is not simply the result of aging and mechanical wear from joint use, nor is primary osteoarthrosis caused by inflammation. Unlike the joint destruction seen in joint diseases with a major inflammatory component, osteoarthrosis consists of a retrogressive sequence of changes in the cells and matrix that result in the loss of structure and function of articular cartilage accompanied by cartilage repair and bone-remodeling reactions^28,143. Because of the repair and remodeling reactions, the degeneration of the articular surface in osteoarthrosis is not uniformly progressive, and the rate of degeneration varies among individuals and among joints. Occasionally, degeneration occurs rapidly, but in most joints it progresses slowly over many years, although it may stabilize or even decrease spontaneously, with at least partial restoration of the articular surface and a decrease in symptoms.

Osteoarthrosis usually involves all of the tissues that form the synovial joint, including articular cartilage, subchondral and metaphyseal bone, synovial tissue, ligaments, joint capsule, and muscles that act across the joint; however, the primary changes consist of loss of articular cartilage, remodeling of subchondral bone, and formation of osteophytes^28,150. The earliest histological changes seen in osteoarthrosis include fraying or fibrillation of the superficial zone of the articular cartilage, extending into the transitional zone; decreased staining for proteoglycans in the superficial and transitional zones; violation of the tidemark by blood vessels from subchondral bone; and remodeling of subchondral bone. Some investigators have postulated that stiffening of subchondral bone due to remodeling precedes and causes degeneration of articular cartilage and that progression of the degeneration requires stiffening of subchondral bone¹³⁶; alternatively, loss of articular cartilage could increase peak stresses on subchondral bone, causing bone-remodeling. It is not clear which of these views is correct, or if either of them is entirely correct, but in most instances degeneration of articular cartilage and remodeling of subchondral bone are both present when symptoms develop, and it is the loss of articular cartilage that leads directly to the loss of joint function.

The earliest sign of osteoarthrosis visible from the articular surface is localized fibrillation or disruption of the most superficial layers of the articular cartilage (Table II). As the disease progresses, the surface irregularities become clefts, more of the articular surface becomes roughened and irregular, and the fibrillation extends deeper into the cartilage until the fissures reach subchondral bone. As the cartilage fissures grow deeper, the superficial tips of the fibrillated cartilage tear, releasing free fragments into the joint space and decreasing the thickness of the cartilage. At the same time, enzymatic degradation of the matrix further decreases the volume of the cartilage^4,49,103,156. Eventually, the progressive loss of articular cartilage leaves only dense and often necrotic eburnated bone.

Many of the mechanisms responsible for the progressive loss of cartilage in primary osteoarthrosis remain unknown, but the process can be divided into three overlapping stages: disruption or alteration of the cartilage matrix, the chondrocytic response to tissue damage, and the decline of the chondrocytic synthetic response and the progressive loss of tissue^{28,88,95,96,99,100,102} (Table III).

In the first stage, either before or with the appearance of fibrillation, the macromolecular framework of the matrix is disrupted or altered at the molecular level and the water content increases^{28,52,53,95,96,100}. While the concentration of type-II collagen remains constant, decreases in the aggregation of proteoglycans, the concentration of aggrecans, and the length of the glycosaminoglycan chains usually accompany the increase in water content. At the same time, alterations in the collagenous framework, including changes in the relationships between the minor collagens and the collagen fibrils, may allow swelling of the aggrecan molecules. Disruption or decreased organization of the macromolecular framework, decreased aggrecan concentration and aggregation, decreased length of the glycosaminoglycan chains, and increased water content all increase the permeability (the ease with which water and other molecules move through the matrix) and decrease the stiffness of the matrix; these alterations may increase the vulnerability of the tissue to additional mechanical damage. This first phase may occur as a result of a variety of mechanical insults, such as high-intensity impact or torsional loading of a joint; it may be due to accelerated degradation of matrix macromolecules as a result of joint inflammation; or it may occur as a result of metabolic changes in the tissue that interfere with the ability of chondrocytes to maintain the matrix.

The second stage begins when chondrocytes detect the tissue damage or alterations in osmolarity, charge density, or strain and release mediators that stimulate a cellular response that is often quite brisk. The response consists of both anabolic and catabolic activity as well as proliferation of chondrocytes^{28,43,95,96,99,101,102,104,133}. Anabolic and mitogenic growth factors presumably have an important role in stimulating the synthesis of matrix macromolecules and the proliferation of chondrocytes; clusters or clones of proliferating cells surrounded by newly synthesized matrix molecules constitute one histological hallmark of the chondrocytic response to the degeneration of cartilage^{28,95,96,99,101,102,104,113,157}. Nitric oxide may have a role in the chondrocytic response, as chondrocytes produce this molecule in response to a variety of mechanical and chemical stresses^3,13. It diffuses rapidly and can induce production of the cytokine interleukin-1, which stimulates the expression of metalloproteases that degrade the matrix macromolecules. Fibronectin fragments or other molecules present in damaged tissue may promote continued production of interleukin-1 and enhanced release of proteases^40,68,69,167. Degradation of type-IX and type-XI collagens and other molecules may destabilize the type-II collagen-fibril meshwork, leaving many type-II fibrils intact initially but allowing expansion of aggrecans and increased water content. Disruption of the superficial zone, a decline in aggregation, and an associated loss of aggrecans due to enzymatic degradation increase the stresses on the remaining collagen-fibril network and chondrocytes with joint-loading. Enzymatic degradation also clears damaged and intact matrix components^49,103 and may release anabolic cytokines previously trapped in the matrix that stimulate the synthesis of matrix macromolecules and the proliferation of chondrocytes. In this second stage of the development of osteoarthrosis, the repair response—the increased synthesis of matrix macromolecules and, to a lesser extent, cell proliferation—counters the catabolic effects of the proteases and may stabilize or, in some instances, restore the tissue. The repair response may last for years, and in some patients it reverses the course of osteoarthrosis at least temporarily. Furthermore, some therapeutic interventions have the potential for facilitating the repair response. For example, studies of osteoarthrotic hips and knees after osteotomy have shown that altering the mechanical environment of the joint sometimes stimulates the restoration of an articular surface^{27,29,124,164}.

Failure to stabilize or restore the tissue leads to the third stage in the development of osteoarthrosis: a progressive loss of articular cartilage as well as a decline in the chondrocytic anabolic and proliferative response^{28,95,96,101,102}. This decline could result from the mechanical damage and death of chondrocytes no longer stabilized and protected by a functional matrix, but it also appears to be related to, or initiated by, a down-regulation of the chondrocytic response to anabolic cytokines. This may occur as a result of synthesis and accumulation of molecules in the matrix that bind anabolic cytokines, including decorin, insulin-dependent growth-factor binding protein, and other molecules that can affect cytokine function. The loss of articular cartilage leads to the symptoms of osteoarthrosis (pain and loss of joint function). This loss occurs more frequently with increasing age, possibly because age-related changes in the cartilage matrix and a decrease in the chondrocytic anabolic response compromise the ability of the tissue to maintain and restore itself^35,104,105.

Alterations of the subchondral bone that accompany the degeneration of articular cartilage include increased density of the subchondral bone (subchondral sclerosis); formation of cyst-like bone cavities containing myxoid, fibrous, or cartilaginous tissue; and the appearance of regenerating cartilage within and on the subchondral bone surface. This response is usually most apparent on the periphery of the joint, where osseous and cartilaginous excrescences sometimes form sizable osteophytes. Increased density of subchondral bone resulting from formation of new layers of bone on existing trabeculae is usually the first sign of degenerative joint disease in subchondral bone, but in some joints subchondral cavities appear before a generalized increase in bone density. At the end stage of the disease, the articular cartilage has been completely lost, leaving thickened, dense subchondral bone articulating with a similarly denuded osseous surface. The bone-remodeling combined with the loss of articular cartilage changes the shape of the joint and can lead to shortening of the involved limb, deformity, and instability.

In most synovial joints, growth of osteophytes accompanies the changes in articular cartilage and in subchondral and metaphyseal bone. These fibrous, cartilaginous, and osseous prominences¹ usually develop around the periphery of the joint (marginal osteophytes), usually at the cartilage-bone interface, but they also may appear along the insertions of the joint capsule (capsular osteophytes). Intra-articular osseous excrescences that protrude from degenerating joint surfaces are referred to as central osteophytes¹⁶⁰. Most marginal osteophytes have a cartilaginous surface that closely resembles normal articular cartilage, and they may appear to be an extension of the joint surface. In superficial joints they usually are palpable and may be tender, and in all joints they can restrict motion and contribute to pain with motion. Each joint has a characteristic pattern of osteophyte formation. Osteophytes in the hip usually form around the rim of the acetabulum and in the femoral articular cartilage. A prominent osteophyte along the inferior margin of the humeral articular surface commonly develops in degenerative disease of the glenohumeral joint. Presumably, osteophytes represent a response to the degeneration of articular cartilage and the remodeling of subchondral bone, including the release of anabolic cytokines that stimulate cell proliferation and the formation of osseous and cartilaginous matrices^114,158.

The loss of articular cartilage leads to secondary changes in synovial tissue, ligaments, and capsules and in the muscles that move the involved joint. The synovial membrane often has a mild-to-moderate inflammatory reaction and may contain fragments of articular cartilage¹²⁰. With time, the ligaments, capsules, and muscles become contracted. Decreased use of the joint and a decreased range of motion lead to muscle atrophy. These secondary changes often contribute to the stiffness and weakness associated with osteoarthrosis.

Although the symptoms of osteoarthrosis, primarily pain and stiffness of the joint, result from degeneration of the joint, the severity of the loss of articular cartilage is not necessarily closely related to the severity of the symptoms. Patients who have advanced joint degeneration may have relatively little pain and surprising mobility, while others who have moderate degeneration may have severe symptoms and limited motion. Furthermore, as with the degeneration of cartilage, the clinical syndrome of osteoarthrosis may remain stable; may progress slowly over many years or even decades; may improve temporarily; or, occasionally, may progress rapidly to the point that the patient is completely disabled within a few years after the onset of the disease.

Joint Use and Degeneration of Articular Cartilage

An understanding of the relationships between joint use and joint degeneration forms a critical part of strategies to prevent and treat osteoarthrosis²⁶. Investigations of the effects that running has on animal and human joints indicate that moderate and possibly even strenuous regular activity does not cause or accelerate the development of osteoarthrosis in normal joints (those with normal articular surfaces, alignment, static and dynamic stability, innervation, and muscle control)^21,26,30. Furthermore, cyclical loading of cartilage stimulates matrix synthesis, whereas prolonged static loading or the absence of loading and motion causes degradation of the matrix and, eventually, degeneration of the joint²¹.

Despite the importance of regular activity for the maintenance of joints, some types of repetitive joint use apparently accelerate the development of degenerative joint disease²⁶. Studies of individuals who have certain physically demanding occupations, including farmers, construction workers, metal workers, miners, and pneumatic-drill operators, have suggested that repetitive, intense joint-loading may lead to an early onset of joint degeneration^26,30. Specific activities that have been associated with osteoarthrosis include the repetitive lifting or carrying of heavy objects, an awkward work posture, vibration, continuously repeated movements, and a working speed that is determined by a machine; other studies have suggested that participation in sports or other activities that repetitively expose joints to high levels of impact or torsional loading may increase the probability of joint degeneration^{26,30,135,138-141}.

Individuals who have an abnormal anatomy or function of the joint, including disruption or incongruity of the articular surface, dysplasia, malalignment, instability, disturbances of innervation of the joint or muscles, and inadequate muscle strength or endurance, probably have a greater risk of degenerative joint disease²⁶. Subjecting the joints to loads greater than those that result from normal activities of daily living, especially activities that involve repetitive impact or torsion, presumably increases the risk further. These individuals and those who have early osteoarthrosis can benefit from regular exercise, but they should have a detailed evaluation of their joint structure and function before beginning. In most instances, they would be best advised to select an exercise program that maintains joint motion and muscle strength with minimum loading.

Repair and Regeneration of Articular Cartilage

For at least 250 years, physicians and scientists have sought ways to repair or regenerate the articular surfaces of synovial joints after the loss or degeneration of articular cartilage³². (Repair refers to the restoration of a damaged articular surface with new tissue that resembles but does not duplicate the structure, composition, and function of articular cartilage; regeneration refers to the formation of new tissue indistinguishable from normal articular cartilage^31,33,166.) They made little progress during most of this period, but in the last three decades clinical and basic scientific investigations have shown that implantation of artificial matrices, growth factors, perichondrium, periosteum, and transplanted chondrocytes and mesenchymal stem cells can stimulate the formation of cartilaginous tissue in osteochondral and chondral defects in synovial joints^{23,25,27,31,109}. Other work has demonstrated that loading and motion of the joint can influence the healing of articular cartilage and joints^116,145,146 and that mechanical loading influences the repair process in all tissues that form parts of synovial joints^20,22,33. In addition, review of several operative procedures used to treat osteoarthrosis, including osteotomy, penetration of subchondral bone, and joint distraction and motion, has shown that these procedures can stimulate the formation of new articular surfaces²⁷. The apparent potential of these methods for stimulating the formation of cartilaginous articular surfaces has created great interest on the part of patients, physicians, and scientists; however, the wide variety of methods and approaches for assessing the results has made it difficult to evaluate their relative success in restoring function of the joint and to define the most appropriate current clinical applications.

A better understanding of the lesions and degeneration of articular cartilage, and recognition of the limitations of current treatments, have also contributed to the recent interest in the repair and regeneration of cartilage^19,27-29,32. Advances in the imaging of and the arthroscopic techniques for synovial joints have led to an increased understanding of the frequency and types of chondral defects and have made it possible for orthopaedic surgeons to diagnose and evaluate these lesions with great accuracy⁸⁷. Age-related, non-progressive, superficial fibrillation of cartilage and focal lesions of the articular surface must be distinguished from degeneration of cartilage occurring as part of the syndrome of osteoarthrosis⁹⁸ (Table II). Superficial fibrillation of articular cartilage occurs in many joints in association with increasing age and does not appear to cause symptoms or to affect the function of the joint adversely. Isolated defects of articular cartilage and osteochondral defects appear to result from trauma that often leaves most of the articular surface intact^19,87. These defects commonly occur in adolescents and young adults who wish to maintain a high level of activity, and in some of these individuals they cause joint pain, effusions, and mechanical dysfunction. Although the natural history of isolated chondral and osteochondral defects has not been well defined^94,109,110, clinical experience has shown that, when left untreated, these lesions fail to heal and that defects that involve a major portion of the articular surface may progress to symptomatic degeneration of the joint. Therefore, the treatment of selected isolated chondral and osteochondral defects may help to delay or prevent the development of osteoarthrosis. Because débridement alone produces variable results^27,87, investigators have sought better methods of treatment for these focal defects.

A variety of methods have the potential to stimulate the formation of a new articular surface, including penetration of subchondral bone, osteotomy, joint distraction, use of soft-tissue grafts, cell transplantation, use of growth factors, and use of artificial matrices. The available evidence indicates that the results vary considerably among individuals and that the tissue that forms after these treatments does not duplicate the composition, structure, or mechanical properties of normal articular cartilage (Figs. 1-A, 1-B, and 1-C). However, the regeneration of normal articular cartilage may not be necessary in order for a procedure to be beneficial; in at least some instances, stimulating the formation of articular cartilage repair tissue may decrease symptoms and improve joint function²⁷. Reports of the clinical results of procedures intended to restore a damaged or degenerated articular surface have documented clinical improvement for most (usually more than 75 per cent) of the patients (Table IV)^{9,16,18,23,51,55,59,70,75,81,82,87,119,142,151,154,159,164}. However, these studies have serious limitations: the ages of the patients and the types of defects of the articular surface varied considerably; some series included patients who had advanced degenerative disease, while others included only those who had localized chondral defects in otherwise normal joints; and, as none of the studies were controlled or prospective, the durations of follow-up and the measures of outcome varied. Thus, it is difficult to compare the efficacy of the various approaches for the restoration of articular cartilage. Nonetheless, a review of the results of these procedures provides considerable insight into the potential for the restoration of articular surfaces.

Penetration of Subchondral Bone

Penetration of subchondral bone was the original method developed to stimulate the formation of a new articular surface, and it is still the most commonly used^27,83 (Table IV). In regions with full-thickness loss or advanced degeneration of articular cartilage, penetration of the exposed subchondral bone disrupts subchondral blood vessels, leading to the formation of a fibrin clot over the bone surface^27,33. If the surface is protected from excessive loading, undifferentiated mesenchymal cells migrate into the clot, proliferate, and differentiate into cells with the morphological features of chondrocytes¹⁵². In some instances they form a fibrocartilaginous articular surface, but in others they do not^81,82 (Figs. 1-A, 1-B, 1-C through 2).

Surgeons initially debrided degenerated articular cartilage and drilled into the subchondral bone through arthrotomies, and many patients reported a decrease in symptoms after this procedure^8,64,74,92. Ficat et al. excised damaged cartilage along with underlying subchondral bone for the treatment of degeneration of the articular surface of the patella; they referred to this procedure as spongialization⁵⁵. They reported a good or excellent result in sixty-seven (79 per cent) of eighty-five patients (Table IV). Surgeons have developed various other methods for the penetration of subchondral bone to stimulate the formation of a new cartilaginous surface, including arthroscopic abrasion of the articular surface and the creation of multiple small-diameter defects or fractures with an awl or a similar instrument^27,81-83,87.

Prospective, randomized, controlled trials of arthroscopic abrasion of osteoarthrotic joints have not been reported, to our knowledge, but several authors have reviewed series of patients and have found that these procedures can decrease symptoms due to isolated defects of articular cartilage and osteoarthrosis of the knee^{51,59,81,82,87,154}. Baumgaertner et al. reported less successful results with use of this method in forty-four patients (forty-nine knees); they noted early failure in nineteen knees (39 per cent), and twenty-three knees (47 per cent) had had a failure at the latest follow-up examination⁵. The excellent results decreased from twenty knees (41 per cent) at the time of maximum improvement to twelve knees (24 per cent) at the time of the latest follow-up.

Johnson examined joint surfaces after arthroscopic abrasion and found that, in some individuals, this procedure resulted in the formation of a fibrocartilaginous articular surface that varied in composition, from dense fibrous tissue with little or no type-II collagen to hyaline cartilage-like tissue with predominantly type-II collagen^81,82. He also found that, in many patients who had radiographic evidence of narrowing of the joint space or no radiographically demonstrable joint space, the joint space increased after abrasion. Although the increase in the joint space presumably indicated the formation of a new articular surface, this new surface did not necessarily result in a decrease in the symptoms. Bert and Maschka found radiographic evidence of an increased joint space in thirty (51 per cent) of fifty-nine patients two years after abrasion arthroplasty; however, in eighteen patients (31 per cent), the symptoms were unchanged or more severe^11,12.

Some of the variability in the clinical results of attempts to restore an articular surface by penetration of subchondral bone may be the result of differences in the extent and quality of the repair tissue. However, to our knowledge, no study has documented a relationship between the extent and type of repair tissue and the result with regard to symptoms or function. This suggests that the formation of a new articular surface after the penetration of subchondral bone does not necessarily relieve pain²⁷. The lack of a predictable clinical benefit from the formation of cartilage repair tissue may be due to variability among patients with respect to the severity of the degenerative changes, alignment of the joint, patterns of joint use, age, perception of pain, preoperative expectations, or other factors. It may also be attributable to the inability of the newly formed tissue to replicate the properties of articular cartilage²⁹. Examination of the tissue that forms over the articular surface after the penetration of subchondral bone has shown that it lacks the structure, the composition, the mechanical properties, and in most instances the durability of articular cartilage (Figs. 1-A, 1-B, and 1-C)^{27,29,32,33,115}. Therefore, even though this tissue covers the subchondral bone it may fail to distribute loads across the articular surface in a way that avoids pain with loading and additional degeneration of the joint.

Currently, it is not clear which method of penetration of subchondral bone produces the best new articular surface; differences in the selection of patients and the operative technique among surgeons using the same method make it difficult to compare the efficacy of the different techniques. However, comparison of bone abrasion with subchondral drilling for the treatment of an experimental chondral defect in rabbits showed that, while neither treatment predictably restored the articular surface, drilling appeared to produce better long-term results than did abrasion⁵⁸. This observation fits well with previous experimental work showing that chondral repair tissue that grows up through multiple drill-holes passing from the articular surface into vascularized bone spreads over exposed subchondral bone between the holes and forms a fibrocartilaginous articular surface¹¹⁵. It also suggests that small-diameter holes that leave the bone intact between defects lead to the formation of more stable repair tissue than do abraded bone surfaces⁵⁸.

Despite evidence that the penetration of subchondral bone stimulates the formation of fibrocartilaginous repair tissue, the clinical value of this approach remains uncertain. In contrast with reports of a decrease in symptoms in patients who had degeneration of cartilage and were managed with penetration of subchondral bone^{51,59,81,82,154}, one investigator concluded that, while débridement of the joint can decrease symptoms in many patients, abrasion or drilling of subchondral bone does not benefit patients who have osteoarthrosis of the knee and it may increase symptoms¹¹. In addition, the short periods of follow-up; the lack of well defined evaluations of outcome; the absence of randomized, controlled trials; and the possibility of a substantial placebo effect¹¹⁷ or a decrease in the symptoms due to irrigation of the joint alone^39,48,61,89 make it difficult to define the indications for the penetration of subchondral bone.

Osteotomy

Clinical experience has led many surgeons to accept osteotomy as a method for the treatment of hip and knee joints with localized loss or degeneration of the articular surface²⁷. Osteotomy has not been commonly used for the treatment of osteoarthrosis of joints other than the hip and the knee, but in one study tibial osteotomy produced a good or excellent result in fifteen of eighteen patients who had primary osteoarthrosis of the ankle, a rare condition in which osteoarthrosis develops in the absence of any history of trauma¹⁵⁵. Some surgeons have combined débridement of the joint and penetration of subchondral bone with osteotomy, but this approach is not widely used. In general, an osteotomy is planned in order to decrease loads on the most severely damaged regions of the joint surface, to bring regions of the joint surface that have remaining articular cartilage into opposition with regions that lack articular cartilage, or to correct malalignment that may contribute to symptoms and dysfunction of the joint. Most hip and knee osteotomies performed to treat osteoarthrosis alter the alignment of the joint in the coronal plane (varus and valgus osteotomies); however, some hip osteotomies are done to change the alignment of the joint in the sagittal plane (flexion and extension osteotomies) or to alter the relationship of the joint surfaces by rotation of the femoral head relative to the acetabulum (rotational osteotomies).

The optimum planes and degrees of realignment for specific osteoarthrotic joints have not been defined; nonetheless, clinical experience has shown that osteotomies of the hip and the knee can decrease symptoms and stimulate the formation of a new articular surface²⁷. The decrease in pain could result from a decrease in stresses on regions of the articular surface with the most advanced degeneration of cartilage, a decrease in intraosseous pressure, or the formation of a new articular surface, but the mechanisms of the improvement remain poorly understood²⁷.

Most clinical studies have shown that, in at least some patients, osteotomy leads to a decrease in the radiographic signs of joint degeneration, with the improvement including the resolution of subchondral cysts or radiolucent lines, decreased density of subchondral bone, and increased radiographic joint space²⁷. The latter change may result either from the altered relationship between the articular surfaces or from the formation of a new articular surface; that is, the osteotomy may alter the alignment of the joint to separate previously opposed joint surfaces, or it may rotate a cartilage-covered articular surface into opposition with a surface consisting of exposed bone, thus creating a radiographically visible cartilage space where, before the osteotomy, bone had opposed bone. In a series of 757 intertrochanteric osteotomies performed to treat osteoarthrosis of the hip, the radiographic joint space increased immediately after the procedure in approximately one-third of the patients¹⁶⁴. The increased joint space presumably resulted from alterations in the relationships between the joint surfaces. In another one-third of the patients, the joint space increased during the next eighteen months, and these patients had better clinical results. This suggests that, over eighteen months, a new articular surface developed in some areas of the joint as a result of the altered loading¹⁶⁴. Evidence that hip osteotomy stimulates the formation of fibrocartilaginous tissue over articular surfaces that previously consisted of exposed bone supports this suggestion^37,78.

The treatment of degenerative disease of the knee with osteotomy has also led to an increased radiographic joint space accompanied by decreased density of subchondral bone and, in some patients, the formation of a new fibrocartilaginous articular surface²⁷. Bergenudd et al. biopsied the articular cartilage of the medial femoral condyle at the time of the osteotomy and then again at an average of two years after the osteotomy in nineteen patients who had degenerative disease of the medial side of the knee joint⁹. The biopsies showed formation of a new fibrocartilaginous articular surface in nine patients, no change in eight patients, and deterioration of the articular surface in two patients (Table IV). Radiographs showed that six knees had improved, eleven had remained unchanged, and two had deteriorated. There was no correlation among the histological findings, the radiographic appearance, the postoperative varus-valgus angle, or the clinical results⁹. In a similar study, of fourteen patients, proliferation of a new fibrocartilaginous surface was found on the tibial condyle in eight patients and on the medial femoral condyle in nine patients two years after the osteotomy¹²⁴. The authors of that study also found no correlation between the restoration of an articular surface and the clinical outcome.

Long-term follow-up of patients who were managed with osteotomy for osteoarthrosis of the hip or the knee have shown that the clinical results deteriorate with time^{10,75,106,142,164}. Variables that appear to affect the results of knee osteotomy adversely include an older age; obesity; severe degeneration, instability, or limited motion of the joint; operative overcorrection or undercorrection; and a postoperative loss of correction^10,42,75,106. However, even patients who appear to be optimum candidates for osteotomy and who have a good initial outcome tend to have recurrent pain and evidence of progressive osteoarthrosis with time.

Decreased Contact Pressures of Articular Surfaces Combined with Joint Motion

Several sets of observations suggest that decreased contact pressures of the articular surfaces combined with movement of the joint may stimulate the restoration of an articular surface on osteoarthrotic joints. Before the development of artificial joints, surgeons found that resection of an osteoarthrotic joint surface followed by decreased loading combined with motion of the joint resulted in the formation of fibrocartilaginous tissue over the osseous surfaces^27,29,65. When the degenerated articular surfaces were resected along with some underlying bone, the space between the bone surfaces filled with a fibrin clot and then with granulation tissue. Decreased loading with motion of the resected joint facilitated the formation of opposing fibrocartilaginous surfaces, whereas immobilization and compression could lead to osseous or fibrous ankylosis. Reports have suggested that attempts to decrease loading of the joint by releasing the muscles that act across a degenerated hip joint can decrease symptoms and increase the radiographic cartilage space in some patients^107,137,149; examination of osteoarthrotic joints after osteotomy has shown formation of a new articular surface in some instances (as noted in the discussion of osteotomy).

These observations concerning the effects of decreased contact pressures combined with motion of the joint have recently been supported by clinical studies of the effects of joint distraction and motion with use of external fixators. Aldegheri et al. used distraction that allowed joint motion to manage eighty patients who had a variety of hip disorders². Twenty-four patients who either had inflammatory joint disease or were more than forty-five years old had a poor result, and only four patients who were more than forty-five years old had a good result; in contrast, forty-two of fifty-nine patients who were less than forty-five years old and had osteoarthrosis, dysplasia, avascular necrosis, or chondrolysis had a good result. These results suggest that, at least in patients who are less than forty-five years old, decreased contact pressures and motion of damaged hip-joint surfaces can decrease symptoms. In a recent preliminary report, van Valburg et al. described encouraging results with use of distraction and motion of the joint in eleven patients who had advanced post-traumatic osteoarthrosis of the ankle¹⁵⁹. After application of an Ilizarov device, the joint was distracted 0.5 millimeter each day for five days; the distraction of the articular surfaces was then maintained throughout the course of the treatment. The patients were allowed to walk a few days after the operation, active motion was started between six and twelve weeks postoperatively, and the distraction device was removed after twelve to twenty-two weeks. At an average of twenty months, none of the patients had had an arthrodesis. All eleven patients had less pain, and five were pain-free; six had more motion, and three of six who had radiographs had increased joint space¹⁵⁹ (Table IV). Although that study had important limitations²⁴, the decrease in symptoms and the delay (if not the avoidance) of arthrodesis in all eleven patients indicates that distraction or other methods of decreasing joint contact forces combined with motion of the joint deserve additional evaluation.

Soft-Tissue Grafts

Treatment of osteoarthrotic joints with soft-tissue grafts most often involves débridement of the joint and interposition of soft-tissue grafts consisting of fascia, joint capsule, muscle, tendon, periosteum, or perichondrium between debrided or resected articular surfaces^{27,67,80,121,125,126,128}. The potential benefits include the introduction of a new cell population along with an organic matrix, a decrease in the probability of ankylosis before a new articular surface can form, and some protection of the graft or the host cells from excessive loading. The success of soft-tissue arthroplasty depends not only on the severity of the abnormalities of the joint and on the type of graft but also on postoperative motion to facilitate the generation of a new articular surface^125,126,145.

Animal experiments and clinical experience have shown that perichondrial and periosteal grafts placed in articular cartilage defects can produce new cartilage^27,145. Recently, encouraging results with use of periosteal grafts for the treatment of isolated chondral and osteochondral defects have been reported²³, and other investigators have reported similar positive results with use of perichondrial grafts^50,70. Seradge et al. found that an older age of the patient adversely affected the results of soft-tissue grafts¹⁵¹. They studied the results a minimum of three years after arthroplasty with a graft of rib perichondrium in sixteen metacarpophalangeal joints and twenty proximal interphalangeal joints. Despite the small numbers in their series, the results suggested that increased age adversely affected the results in both groups of joints. Of the patients who had had an arthroplasty of the metacarpophalangeal joint and were available for evaluation, all three who were twenty years old or less, three of the four who were between twenty-one and thirty years old, and only three of the six who were more than thirty years old had a good result. Of the patients who had had an arthroplasty of the interphalangeal joint and were available for evaluation, four of the five who were twenty years old or less, four of the six who were between twenty-one and thirty years old, and only one of the three who were more than thirty years old had a good result (Table IV). No patient who was more than forty years old had a good result with either type of arthroplasty. Those authors concluded that arthroplasty with a perichondrial graft could be used for the treatment of post-traumatic osteoarthrosis of the metacarpophalangeal joints and the proximal interphalangeal joints of the hand in young patients.

The clinical observation that perichondrial grafts produced the best results in younger patients¹⁵¹ is in agreement with the concept that age may adversely affect the ability of undifferentiated cells or chondrocytes to form an articular surface or that, with age, the population of cells that can form an articular surface declines³⁵. The age-related differences in the ability of cells to form a new articular surface may also help to explain some of the variability in the results of other procedures, including osteotomy or procedures that penetrate subchondral bone; younger people may have greater potential to produce a more effective articular surface when all other factors are equal.

Cell Transplantation

The limited ability of host cells to restore articular surfaces^29,32 has led investigators to seek methods of transplanting cells that can form cartilage into chondral and osteochondral defects. Experimental work has shown that both chondrocytes and undifferentiated mesenchymal cells placed in articular cartilage defects survive and produce a new cartilage matrix²⁷ (Fig. 3). Wakitani et al. estimated that hyaline cartilage developed in thirty (75 per cent) of forty osteochondral defects in rabbits that had been treated with allograft articular chondrocytes embedded in collagen gels, while only fibrocartilage developed in twenty-four control defects¹⁶³. Other investigators have reported similar results with chondrocyte transplantation^{76,77,122,144,153}. Recently, Brittberg et al. compared the results of the treatment of chondral defects in the articular surface of the patella in rabbits with use of periosteal grafts alone; with use of carbon-fiber scaffolds and periosteum; with use of autologous chondrocytes and periosteum; and with use of autologous chondrocytes, carbon-fiber scaffolds, and periosteum^15,17. They found that the addition of autologous chondrocytes improved the histological quality and amount of repair tissue. Other studies have shown that mesenchymal cells aspirated from bone can produce cartilaginous tissue in goats³⁶ and that mesenchymal stem cells can repair large osteochondral defects in rabbits^161,162.

Brittberg et al. also described the use of transplants of autologous chondrocytes for the treatment of localized cartilage defects of the femoral condyle or the patella in twenty-three patients¹⁸. Chondrocytes were obtained from the patients, cultured for fourteen to twenty-one days, and then injected into the area of the defect and covered with a flap of periosteum. Two years or more after transplantation, fourteen of the sixteen patients who had a condylar defect and two of the seven who had a patellar defect had a good or excellent clinical result. Biopsy of the site of the defect showed hyaline-like cartilage in eleven of the sixteen femoral and one of the seven patellar defects¹⁸. More recently, the results in a larger group of patients were reported²³. More than two years after the transplantation of chondrocytes for the treatment of chondral defects of the knee, forty-seven of sixty-six patients had improved function.

These results suggest that the transplantation of chondrocytes combined with the use of a periosteal graft can promote the restoration of an articular surface in humans. However, more work is needed to assess the function and durability of the new tissue, to determine if it improves joint function and delays or prevents joint degeneration, and to ascertain if this approach will be beneficial in the treatment of osteoarthrotic joints.

Growth Factors

Growth factors influence a variety of cell activities, including proliferation, migration, matrix synthesis, and differentiation. Many of these factors, including fibroblast growth factors, insulin-like growth factors, and transforming growth factor-ß, have been shown to affect chondrocyte metabolism and chondrogenesis^27,33. Bone matrix contains a variety of these molecules, including transforming growth factor-ß, insulin-like growth factors, bone morphogenetic proteins, and platelet-derived growth factors^33,34. In addition, mesenchymal cells, endothelial cells, and platelets produce many of these factors. Thus, osteochondral injuries and exposure of bone due to loss of articular cartilage may release these agents that affect the formation of cartilage repair tissue, and they probably have an important role in the formation of new articular surfaces after currently used operative procedures, including resection arthroplasty, penetration of subchondral bone, soft-tissue grafts, and possibly osteotomy.

Local treatment of chondral or osteochondral defects with growth factors has the potential to stimulate the restoration of an articular surface that is superior to that formed after the penetration of subchondral bone alone, especially in joints with normal alignment and a normal range of motion and with limited regions of cartilage damage. A recent experimental study of the treatment of partial-thickness cartilage defects with enzymatic digestion of proteoglycans that inhibit adhesion of cells to articular cartilage, followed by implantation of a fibrin matrix and timed release of transforming growth factor-ß, showed that this growth factor can stimulate cartilage repair^72,73 (Figs. 4 and 5). The cells that filled the chondral defects migrated into the defects from the synovial tissue and formed a fibrous matrix. Despite the promise of this approach, the wide variety of growth factors, their multiple effects, their interactions, the possibility that the responsiveness of cells to growth factors may decline with age^35,105,132, and the limited understanding of their effects in osteoarthrotic joints make it difficult to develop a simple strategy for the use of these agents to manage patients who have osteoarthrosis. However, the development of growth-factor-based treatments for younger patients who have an isolated chondral or osteochondral defect and early degenerative changes of cartilage appears promising.

Artificial Matrices

The treatment of chondral defects with growth factors or cell transplants requires a method of delivering and, in most instances, at least temporarily stabilizing the growth factors or cells in the defect. The success of these approaches therefore often depends on an artificial matrix (Figs. 4 and 5). In addition, an artificial matrix may allow and, in some instances, stimulate ingrowth of host cells, matrix formation, and binding of new cells and matrix to host tissue¹³⁰. Investigators have found that implants formed from a variety of biological and non-biological materials, including treated cartilage and bone matrices, collagens, collagens and hyaluronan, fibrin, carbon fiber, hydroxyapatite, porous polylactic acid, polytetrafluoroethylene, polyester, and other synthetic polymers, facilitate the restoration of an articular surface²⁷. A lack of data makes it difficult to compare the relative merits of different types of artificial matrices and to evaluate the possibility that some implanted materials may cause synovitis¹⁰⁸; however, the available evidence indicates that at least some types of artificial matrices can contribute to the restoration of an articular surface. In animal experiments, fibrous polyglycolic acid, collagen gels, and fibrin have proved to be effective matrices for the implantation of cells, and fibrin has been used to implant and allow timed release of a growth factor^57,66,72,147. The treatment of osteochondral defects with use of carbon-fiber pads in rats and rabbits resulted in the restoration of a smooth articular surface consisting of firm fibrous tissue that filled the pads¹¹⁹. Use of the same approach to treat osteochondral defects of the knee in humans produced a satisfactory result in thirty-six (77 per cent) of forty-seven patients who were evaluated clinically and arthroscopically three years after the operation¹¹⁹. Brittberg et al. also studied the use of carbon-fiber pads for the treatment of articular surface defects; they noted a good or excellent result in thirty (83 per cent) of thirty-six patients at an average of four years¹⁶ (Table IV).

Transplantation of Articular Cartilage

The transplantation of articular cartilage as part of an osteochondral graft has been shown to be a clinically effective method of replacing focal regions of damaged articular cartilage^{7,14,41,44,60,63,91,93,111,112,129,165}, and experimental work has suggested that osteochondral grafts provide better restoration of articular surfaces than does the natural repair response to an acute osteochondral defect⁴⁵. Compared with methods designed to repair or regenerate a new articular surface, osteochondral grafts have the advantage of providing a fully formed articular cartilage matrix and the potential for transplanting viable chondrocytes that can maintain the matrix^44,127,148. Osteochondral grafts also can restore subchondral bone and the contour of the joint in patients who have osteochondral defects or incongruity of the joint.

Autologous Grafts

Because of the small number of possible donor sites from which osteochondral autologous grafts may be obtained, use of these grafts has been limited to selected localized regions of damaged articular cartilage. In a small number of patients, surgeons have replaced damaged or lost articular surfaces with autologous grafts of articular cartilage obtained from the patella, the femoral condyle, and the proximal part of the fibula^{14,38,79,84,129,165,168}, and the results have shown that this technique can restore an articular surface. In two studies, osteochondral autologous grafts from the patella used to replace portions of the tibial articular surface healed and provided satisfactory function of the joint for more than a decade^79,165. Outerbridge et al. treated osteochondral defects of the femoral condyle with patellar osteochondral grafts in ten patients and found that function of the knee improved and symptoms were alleviated in all patients at an average of six and one-half years after transplantation¹²⁹.

Allografts

Because of their greater availability and because they can be prepared in any size, osteochondral allografts have been used more frequently than autologous surfaces^{6,7,41,56,60,63,90,91,93,111,112}. Clinical experience with fresh and frozen osteochondral allografts has shown that they can heal to the host tissue and restore an articular surface. The use of fresh osteochondral allografts to replace portions of damaged tibial plateaus decreased pain and improved function in ten of twelve patients who were followed for more than two years⁹⁰. Of forty knees that had had transplantation of fresh osteochondral allografts because of localized degeneration of the articular surface, thirty-one had healing of the graft and nine had failure of the graft at two to ten years¹¹². Of the thirty-one successful transplants, thirteen had an excellent result, fourteen had a good result, and four had a fair result. The authors recommended use of fresh osteochondral allografts for the treatment of post-traumatic degenerative osteoarthrosis of the patella, post-traumatic osteoarthrosis, and traumatic defects of the tibial plateau as well as for osteochondritis dissecans and avascular necrosis of the femoral condyle. They advised against use of the grafts for the treatment of degenerative osteoarthrosis of the knee involving both the femur and the tibia, and only three of these ten procedures succeeded.

Gross et al. studied the results of ninety-two fresh osteochondral allografts used to treat post-traumatic osteoarticular defects of the knee⁶³. They reported a successful result in sixty-nine knees (75 per cent) at five years, in fifty-nine knees (64 per cent) at ten years, and in fifty-eight knees (63 per cent) at fourteen years. Flynn et al. reported results with use of frozen osteochondral allografts that compared favorably with those with use of fresh allografts for the treatment of localized defects of the distal femoral articular surface⁵⁶. Those authors emphasized that use of frozen allografts permits the operative reconstruction to be performed electively and allows time for more extensive testing of the donors for possible viral or bacterial infections.

Overview

The degeneration of articular cartilage as part of the clinical syndrome of osteoarthrosis is one of the most common causes of pain and disability in middle-aged and older people. The strong correlation between increasing age and the prevalence of osteoarthrosis, and recent evidence of important age-related changes in the function of chondrocytes, suggest that age-related changes in articular cartilage can contribute to the development and progression of osteoarthrosis. Although the mechanisms responsible for osteoarthrosis remain poorly understood, lifelong moderate use of normal joints does not increase the risk. Thus, the degeneration of normal articular cartilage is not simply the result of aging and mechanical wear. However, high-impact and torsional loads may increase the risk of degeneration of normal joints, and individuals who have an abnormal joint anatomy, joint instability, disturbances of joint or muscle innervation, or inadequate muscle strength or endurance probably have a greater risk of degenerative joint disease.

Recent work has shown the potential for the restoration of an articular surface. Currently, surgeons frequently debride joints and penetrate subchondral bone, as well as perform osteotomies, with the intent of decreasing symptoms and restoring or maintaining a functional articular surface. The results of these procedures vary considerably among patients. Clinical and experimental work has shown the important influence of loading and motion on the healing of articular cartilage and joints. Experimental studies have revealed that transplantation of chondrocytes and mesenchymal stem cells; use of periosteal and perichondrial grafts, synthetic matrices, and growth factors; and other methods have the potential to stimulate the formation of a new articular surface.

The long-term follow-up of small series of patients has shown that the transplantation of osteochondral autologous grafts and allografts can be effective for the treatment of focal defects of articular cartilage in selected patients. Thus far, none of these methods has been shown to predictably restore a durable articular surface to an osteoarthrotic joint, and it is unlikely that any one of them will be uniformly successful. Rather, the available clinical and experimental evidence indicates that future optimum methods for the restoration of articular surfaces will begin with a detailed analysis of the structural and functional abnormalities of the involved joint and the patient's expectations for future use of the joint. On the basis of this analysis, the surgeon will develop a treatment plan that potentially combines correction of mechanical abnormalities (including malalignment, instability, and intra-articular causes of mechanical dysfunction), débridement that may or may not include limited penetration of subchondral bone, and applications of growth factors or implants that may consist of a synthetic matrix that incorporates cells or growth factors or use of transplants followed by a postoperative course of controlled loading and motion.

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TABLE I KNOWN CAUSES OF JOINT DEGENERATION (SECONDARY OSTEOARTHROSIS)

Cause	Presumed Mechanism
Intra-articular fracture	Damage to articular cartilage or incongruity of joint, or both

High-intensity-impact joint-loading	Damage to articular cartilage or subchondral bone, or both

Ligament injuries	Instability of joint

Dysplasia of joint and cartilage (developmental and hereditary)	Abnormal shape of joint or abnormal articular cartilage, or both

Aseptic necrosis	Bone necrosis leads to collapse of articular surface and incongruity of joint

Acromegaly	Overgrowth of articular cartilage produces incongruity of joint or abnormal cartilage, or both

Paget disease	Distortion or incongruity of joint due to bone-remodeling

Ehlers-Danlos syndrome	Instability of joint

Gaucher disease (hereditary deficiency of enzyme glucocerebrosidase, leading to accumulation of glucocerebroside)	Bone necrosis or pathological fracture leads to incongruity of joint

Stickler syndrome (progressive, hereditary arthro-ophthalmopathy)	Abnormal development of joint or articular cartilage, or both

Infection of joint (inflammation)	Destruction of articular cartilage

Hemophilia	Multiple joint hemorrhages

Hemochromatosis (excess deposition of iron in multiple tissues)	Mechanism unknown

Ochronosis (hereditary deficiency of enzyme homogentisic acid oxidase leading to accumulation of homogentisic acid)	Deposition of homogentisic acid polymers in articular cartilage

Calcium pyrophosphate deposition disease	Accumulation of calcium pyrophosphate crystals in articular cartilage

Neuropathic arthropathy (Charcot joints due to syphilis, diabetes mellitus, syringomyelia, myelomeningocele, leprosy, congenital insensitivity to pain, amyloidosis)	Loss of proprioception and joint sensation results in increased impact loading and torsion, instability of joint, and intra-articular fracture

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TABLE I KNOWN CAUSES OF JOINT DEGENERATION (SECONDARY OSTEOARTHROSIS)

Cause	Presumed Mechanism
Intra-articular fracture	Damage to articular cartilage or incongruity of joint, or both

High-intensity-impact joint-loading	Damage to articular cartilage or subchondral bone, or both

Ligament injuries	Instability of joint

Dysplasia of joint and cartilage (developmental and hereditary)	Abnormal shape of joint or abnormal articular cartilage, or both

Aseptic necrosis	Bone necrosis leads to collapse of articular surface and incongruity of joint

Acromegaly	Overgrowth of articular cartilage produces incongruity of joint or abnormal cartilage, or both

Paget disease	Distortion or incongruity of joint due to bone-remodeling

Ehlers-Danlos syndrome	Instability of joint

Gaucher disease (hereditary deficiency of enzyme glucocerebrosidase, leading to accumulation of glucocerebroside)	Bone necrosis or pathological fracture leads to incongruity of joint

Stickler syndrome (progressive, hereditary arthro-ophthalmopathy)	Abnormal development of joint or articular cartilage, or both

Infection of joint (inflammation)	Destruction of articular cartilage

Hemophilia	Multiple joint hemorrhages

Hemochromatosis (excess deposition of iron in multiple tissues)	Mechanism unknown

Ochronosis (hereditary deficiency of enzyme homogentisic acid oxidase leading to accumulation of homogentisic acid)	Deposition of homogentisic acid polymers in articular cartilage

Calcium pyrophosphate deposition disease	Accumulation of calcium pyrophosphate crystals in articular cartilage

Neuropathic arthropathy (Charcot joints due to syphilis, diabetes mellitus, syringomyelia, myelomeningocele, leprosy, congenital insensitivity to pain, amyloidosis)	Loss of proprioception and joint sensation results in increased impact loading and torsion, instability of joint, and intra-articular fracture

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TABLE II DIFFERENCES BETWEEN CHANGES IN ARTICULAR CARTILAGE DUE TO AGING AND THOSE DUE TO DEGENERATION IN OSTEOARTHROSIS^26,104

	Aging	Osteoarthrosis
Structure	Stable, localized, superficial fibrillation	Progressive, superficial fibrillation; fibrillation and fragmentation extending to subchondral bone; loss of tissue (decreased thickness of cartilage with complete loss in some regions); formation of fibro-cartilaginous repair tissue

Cells	Decreased density of chondrocytes with skeletal growth, alteration in synthetic activity (smaller, more variable aggrecans), decreased response to growth factors, decreased synthetic activity	Initial increase in synthetic and proliferative activity, loss of chondrocytes, eventual decreased synthetic activity, increased degradative enzyme activity, appearance of fibroblast-like cells in regions of fibro-cartilaginous repair tissue

Matrix	Decreased concentration of water, loss of large proteoglycan aggregates (decreased stability of aggregates), increased concentration of decorin, accumulation of degraded molecules (aggrecan and link protein fragments), increased collagen cross-linking, increased diameter of and variability in collagen fibrils, decreased tensile strength and stiffness in superficial layers	Initial increase in water content and, in some instances, in concentration of proteoglycans; disruption of collagenous macromolecular organization; progressive degradation and loss of proteoglycans, hyaluronan, and collagens; increased concentration of fibronectin; increased permeability and loss of tensile and compressive stiffness and strength

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TABLE II DIFFERENCES BETWEEN CHANGES IN ARTICULAR CARTILAGE DUE TO AGING AND THOSE DUE TO DEGENERATION IN OSTEOARTHROSIS^26,104

	Aging	Osteoarthrosis
Structure	Stable, localized, superficial fibrillation	Progressive, superficial fibrillation; fibrillation and fragmentation extending to subchondral bone; loss of tissue (decreased thickness of cartilage with complete loss in some regions); formation of fibro-cartilaginous repair tissue

Cells	Decreased density of chondrocytes with skeletal growth, alteration in synthetic activity (smaller, more variable aggrecans), decreased response to growth factors, decreased synthetic activity	Initial increase in synthetic and proliferative activity, loss of chondrocytes, eventual decreased synthetic activity, increased degradative enzyme activity, appearance of fibroblast-like cells in regions of fibro-cartilaginous repair tissue

Matrix	Decreased concentration of water, loss of large proteoglycan aggregates (decreased stability of aggregates), increased concentration of decorin, accumulation of degraded molecules (aggrecan and link protein fragments), increased collagen cross-linking, increased diameter of and variability in collagen fibrils, decreased tensile strength and stiffness in superficial layers	Initial increase in water content and, in some instances, in concentration of proteoglycans; disruption of collagenous macromolecular organization; progressive degradation and loss of proteoglycans, hyaluronan, and collagens; increased concentration of fibronectin; increased permeability and loss of tensile and compressive stiffness and strength

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TABLE III STAGES IN THE DEVELOPMENT AND PROGRESSION OF DEGENERATION OF ARTICULAR CARTILAGE IN OSTEOARTHROSIS^95-97,102

Stage	Description
I: Disruption or alteration of cartilage matrix	Disruption or alteration of macromolecular framework of matrix associated with increase in concentration of water that may be caused by mechanical insults, degradation of matrix macromolecules, or alterations of chondrocyte metabolism. At first, concentration of type-II collagen remains unchanged, but collagen meshwork may be damaged, and concentration of aggrecans and degree of proteoglycan aggregation decrease.

II: Response of chondrocytes to disruption or alteration of matrix	When chondrocytes detect a disruption or alteration of their matrix, they can respond by increasing synthesis and degradation of the matrix and by proliferating. Their response may restore tissue, maintain tissue in an altered state, or increase volume of cartilage. They may sustain an increased level of activity for years.

III: Decline in response of chondrocytes	Failure of chondrocytic response to restore or maintain tissue leads to loss of articular cartilage accompanied or preceded by decline in chondrocytic response. The causes for this decline remain poorly understood, but they may partially result from mechanical damage to tissue with injury to chondrocytes and down-regulation of chondrocytic response to anabolic cytokines.

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TABLE III STAGES IN THE DEVELOPMENT AND PROGRESSION OF DEGENERATION OF ARTICULAR CARTILAGE IN OSTEOARTHROSIS^95-97,102

Stage	Description
I: Disruption or alteration of cartilage matrix	Disruption or alteration of macromolecular framework of matrix associated with increase in concentration of water that may be caused by mechanical insults, degradation of matrix macromolecules, or alterations of chondrocyte metabolism. At first, concentration of type-II collagen remains unchanged, but collagen meshwork may be damaged, and concentration of aggrecans and degree of proteoglycan aggregation decrease.

II: Response of chondrocytes to disruption or alteration of matrix	When chondrocytes detect a disruption or alteration of their matrix, they can respond by increasing synthesis and degradation of the matrix and by proliferating. Their response may restore tissue, maintain tissue in an altered state, or increase volume of cartilage. They may sustain an increased level of activity for years.

III: Decline in response of chondrocytes	Failure of chondrocytic response to restore or maintain tissue leads to loss of articular cartilage accompanied or preceded by decline in chondrocytic response. The causes for this decline remain poorly understood, but they may partially result from mechanical damage to tissue with injury to chondrocytes and down-regulation of chondrocytic response to anabolic cytokines.

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TABLE IV SELECTED CLINICAL REPORTS OF METHODS OF RESTORING AN ARTICULAR SURFACE

Authors	No. of Patients, Joints, or Defects	Results	Comments
Excision of damaged cartilage and underlying bone (spongialization)
Fical et al.⁵⁵	85 patients (patellae)	67 (79%) good or excellent	Used for treatment of patellar chondral lesions

Joint débridement and penetration of subchondral bone
Ewing⁵¹	223 knees	163 (73%) improved	Increased severity of joint disease decreased probability of good result
Friedman et al.⁵⁹	73 knees	44 (60%) improved, 25 (34%) unchanged, 4 (5%) worse	Patients <40 yrs. old had better results
Johnson^81,82	>400 knees	75% satisfactory	12% of patients were symptom-free at 2 yrs.
Sprague¹⁵⁴	69 knees	51 (74%) good, 7 (10%) fair, 11 (16%) poor
Levy et al.⁸⁷	15 knees	6 excellent, 9 good, 0 fair or poor	All patients were competitive soccer players who had isolated chondral defects

Perichondrial grafts
Seradge et al.¹⁵¹	16 metacarpophalangeal joints	3 of 3 patients =20 yrs. old, 3 of 4 21—30 yrs. old, and 3 of 6 >30 yrs. old had good result	No patient >40 yrs. old had good result
	20 prox. interphalangeal joints	4 of 5 patients =20 yrs. old, 4 of 6 21—30 yrs. old, and 1 of 3 >30 yrs. old had good result
Homminga et al.⁷⁰	25 patients (30 defects [knees])	Mean score on knee-function scale improved; 28 (93%) defects filled with cartilaginous tissue	Biopsy showed hyaline tissue; results not related to age

Distraction of joint
van Valburg et al.¹⁵⁹	11 patients (11 ankles)	At average of 20 mos., all patients had less pain and 5 were pain-free; 3 of 6 patients who had radiographs had increased joint space	No patient had arthrodesis

Osteotomy
Weisl¹⁶⁴	757 hips	Joint space increased immediately in approx. 1/3 of patients and after 18 mos. in another 1/3; approx. 2/3 had relief of pain for 5 yrs.; after 10 yrs., only approx. 1/4 had relief	Better results in patients with increased joint space and in those <70 yrs. old who had unilateral disease
Reigstad and Grønmark¹⁴²	103 hips	70% had good result at 1 yr.; 51%, at 5 yrs.; and 30%, at 10 yrs.
Bergenudd et al.⁹	19 patients (knees)	Formation of new fibrocartilaginous surface in 9 patients, no change in 8, and deterioration of articular surface in 2	No correlation among histological findings, radiographic appearance, postop. varus-valgus angle, or clinical results
Insall et al.⁷⁵	95 knees	97% had good or excellent result at 2 yrs. and 85%, at 5 yrs.; 15% were pain-free at 9 yrs.

Carbon-fiber matrix
Muckle and Minns¹¹⁹	47 patients (knees)	36 (77%) had satisfactory result at average of 3 yrs.	No synovitis
Brittberg et al.¹⁶	36 patients (knees)	30 (83%) had good or excellent result at average of 4 yrs.	Good relief of pain, no adverse effects

Autologous chondrocyte transplantation
Brittberg et al.¹⁸	23 patients (knees)	14 of 16 patients who had femoral defect and 2 of 7 who had patellar defect had good or excellent result	Locking of joint eliminated, swelling and pain reduced
Buckwalter²³	66 patients (knees)	47 (71%) improved

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TABLE IV SELECTED CLINICAL REPORTS OF METHODS OF RESTORING AN ARTICULAR SURFACE

Authors	No. of Patients, Joints, or Defects	Results	Comments
Excision of damaged cartilage and underlying bone (spongialization)
Fical et al.⁵⁵	85 patients (patellae)	67 (79%) good or excellent	Used for treatment of patellar chondral lesions

Joint débridement and penetration of subchondral bone
Ewing⁵¹	223 knees	163 (73%) improved	Increased severity of joint disease decreased probability of good result
Friedman et al.⁵⁹	73 knees	44 (60%) improved, 25 (34%) unchanged, 4 (5%) worse	Patients <40 yrs. old had better results
Johnson^81,82	>400 knees	75% satisfactory	12% of patients were symptom-free at 2 yrs.
Sprague¹⁵⁴	69 knees	51 (74%) good, 7 (10%) fair, 11 (16%) poor
Levy et al.⁸⁷	15 knees	6 excellent, 9 good, 0 fair or poor	All patients were competitive soccer players who had isolated chondral defects

Perichondrial grafts
Seradge et al.¹⁵¹	16 metacarpophalangeal joints	3 of 3 patients =20 yrs. old, 3 of 4 21—30 yrs. old, and 3 of 6 >30 yrs. old had good result	No patient >40 yrs. old had good result
	20 prox. interphalangeal joints	4 of 5 patients =20 yrs. old, 4 of 6 21—30 yrs. old, and 1 of 3 >30 yrs. old had good result
Homminga et al.⁷⁰	25 patients (30 defects [knees])	Mean score on knee-function scale improved; 28 (93%) defects filled with cartilaginous tissue	Biopsy showed hyaline tissue; results not related to age

Distraction of joint
van Valburg et al.¹⁵⁹	11 patients (11 ankles)	At average of 20 mos., all patients had less pain and 5 were pain-free; 3 of 6 patients who had radiographs had increased joint space	No patient had arthrodesis

Osteotomy
Weisl¹⁶⁴	757 hips	Joint space increased immediately in approx. 1/3 of patients and after 18 mos. in another 1/3; approx. 2/3 had relief of pain for 5 yrs.; after 10 yrs., only approx. 1/4 had relief	Better results in patients with increased joint space and in those <70 yrs. old who had unilateral disease
Reigstad and Grønmark¹⁴²	103 hips	70% had good result at 1 yr.; 51%, at 5 yrs.; and 30%, at 10 yrs.
Bergenudd et al.⁹	19 patients (knees)	Formation of new fibrocartilaginous surface in 9 patients, no change in 8, and deterioration of articular surface in 2	No correlation among histological findings, radiographic appearance, postop. varus-valgus angle, or clinical results
Insall et al.⁷⁵	95 knees	97% had good or excellent result at 2 yrs. and 85%, at 5 yrs.; 15% were pain-free at 9 yrs.

Carbon-fiber matrix
Muckle and Minns¹¹⁹	47 patients (knees)	36 (77%) had satisfactory result at average of 3 yrs.	No synovitis
Brittberg et al.¹⁶	36 patients (knees)	30 (83%) had good or excellent result at average of 4 yrs.	Good relief of pain, no adverse effects

Autologous chondrocyte transplantation
Brittberg et al.¹⁸	23 patients (knees)	14 of 16 patients who had femoral defect and 2 of 7 who had patellar defect had good or excellent result	Locking of joint eliminated, swelling and pain reduced
Buckwalter²³	66 patients (knees)	47 (71%) improved