JBJS | Suppression of Osteoblast Function by Titanium Particles*†

The Journal of Bone & Joint Surgery, Volume 79, Issue 1

Articles | January 01, 1997

Suppression of Osteoblast Function by Titanium Particles*†

JIANLING YAO, M.D.‡; GABRIELLA CS-SZABÓ, PH.D.‡; JOSHUA J. JACOBS, M.D.‡; KLAUS E. KUETTNER, PH.D.‡; TIBOR T. GLANT, M.D., PH.D.‡, CHICAGO, ILLINOIS

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Investigation performed at the Departments of Biochemistry and Orthopedic Surgery, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago

The Journal of Bone & Joint Surgery. 1997; 79:107-12

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Abstract

In order to understand the effect of particulate debris on osteoblast function, we studied the effect of different particles, including titanium and polystyrene, on bone collagen mRNA (messenger RNA) with the use of Northern blot hybridization analysis, and we studied the effect of the particles on the biosynthesis of bone collagen with analysis of ³H-proline incorporation and with the Western blot technique. The steady-state levels of mRNA for procollagens a₁(I) and a₁(III) were markedly suppressed in human MG-63 osteoblast-like cells exposed to phagocytosable titanium particles that were smaller than three micrometers. Both titanium and polystyrene particles smaller than three micrometers suppressed the expression of the gene that codes for collagen, and the suppression of the expression of the gene was related to the size but not to the composition of the particles. The biosynthesis of both type-I and type-III collagen also was decreased in cells that had been treated with titanium particles. Neither the viability nor the proliferation of cells was affected by particulate debris. These data indicate that phagocytosable titanium particles can significantly suppress the expression of the gene that codes for collagen in osteoblast-like cells (p < 0.05).

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Introduction

Introduction | Materials and Methods | Results | Discussion | References

Total hip arthroplasty has provided dramatic pain relief and improvement in function for millions of patients who have end-stage arthritis or osteoarthrosis. However, periprosthetic osteolysis after total hip arthroplasty is a major clinical problem and can lead to aseptic loosening of prostheses inserted with or without cement. In addition, periprosthetic osteolysis may manifest as a focal process in the absence of loosening, resulting in formidable problems for reconstruction^21,23,32.

A common finding during revision of a failed total hip arthroplasty is the formation of an interfacial soft-tissue membrane that contains fibroblasts, macrophages, and foreign-body giant cells^17,19,26 associated with particulate wear debris^5,19,31. It has been hypothesized that the interaction of particulate wear debris with these phagocytic cells results in the activation of the cells, which in turn produce mediators that provoke a cascade of osteolytic events^13,16,17. Extensive in vitro studies have shown that macrophages can be activated by polymeric or metallic particles, can release mediators of bone resorption, and can show bone-resorbing activity^6,8,14. Fibroblasts stimulated by particles of debris also may play an important role in periprosthetic osteolysis by enhancing the synthesis of metalloproteinases^22,33,34.

The literature, however, contains little information about the direct interaction between particulate debris and osteoblasts. This interaction may provide important insights into the pathogenesis of periprosthetic osteolysis, as normal maintenance of bone relies on the well balanced coordination of the formation and resorption of bone. Either the decreased formation of bone by osteoblasts or the bone-resorbing activity by osteoclasts may disturb bone-remodeling processes and result in osteolysis¹¹. As the interfacial membrane may provide access for particles of wear debris to enter the periprosthetic space^22,27 and to affect the formation of bone by osteoblasts, it is important to understand the responses of osteoblasts and the alterations of their function after exposure to particles of wear debris. The purpose of the present study was to determine the in vitro response of osteoblast-like cells to particles with respect to the expression of bone collagen mRNA (messenger RNA) and to the biosynthesis of bone collagen.

*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 Grants AR41634 and AR39310 and the University Committee on Research of Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois.

†Read in part at the Annual Meeting of the Orthopaedic Research Society, Orlando, Florida, February 14, 1995.

‡Departments of Biochemistry (J. Y. and G. C.-S.) and Orthopedic Surgery (J. J. J., K. E. K., and T. T. G.), Rush-Presbyterian-St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, Illinois 60612. Please address requests for reprints to Dr. Glant.

†Read in part at the Annual Meeting of the Orthopaedic Research Society, Orlando, Florida, February 14, 1995.

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Fig. 1 Autoradiograph of Northern blot analysis, showing the expression of mRNAs for procollagen a1(I) and a1(III) in human MG-63 osteoblast-like cells challenged with small titanium particles (one to three micrometers). The lowest panel shows the corresponding RNAs that were transferred onto the GeneScreen Plus membranes (New England Nuclear, Boston, Massachusetts) and visualized by ethidium bromide. The autoradiographs of the Northern blot hybridizations were essentially the same in three independent experiments. A: Dose-dependent responses. The confluent cells were incubated for twenty-four hours in the absence (C) or the presence of titanium particles at various concentrations (T1 = 0.01 per cent, T2 = 0.05 per cent, and T3 = 0.1 per cent). B: Time-dependent responses. The cells were incubated with 0.05 per cent titanium particles (T) or without them (C) for various time-periods, as indicated.

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Fig. 2 Autoradiograph of Northern blot analysis showing the expression of mRNAs for procollagen a1(I) and a1(III) in human MG-63 osteoblast-like cells incubated for forty-eight hours with various particles at a concentration of 0.05 per cent. The lowest panel shows the responses of corresponding RNAs. The conditions for Northern blot hybridization were the same as those described in Figure 1. A: The cells were untreated (lane 1) or treated with small (one to three-micrometer) titanium particles (lane 2), large (twenty-one to eighty-five-micrometer) titanium particles (lane 3), small (1.14 ± 0.007-micrometer) polystyrene particles (lane 4), large (21.1 ± 4.09-micrometer) polystyrene particles (lane 5), or small (0.7 to 1.3-micrometer) silver particles (lane 6). B: The cells were incubated, for forty-eight hours, without titanium particles (lane 7), with small (one to three-micrometer) titanium particles (lane 8), or with particle-free medium from small titanium particles that had been preincubated alone without cells (lane 9).

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Fig. 3 Graph showing the effect of small titanium particles on collagen synthesis in MG-63 cells. The confluent cells were unchallenged or were challenged with titanium particles (one to three micrometers, at a concentration of 0.05 per cent) for seventy-two hours and labeled with L-[2,3,4,5-³H]proline (twenty-five microcuries per milliliter). The pepsin-resistant collagens (³H-proline-labeled materials) were measured in culture medium (CM) and cell lysates (CL) separately. The bars represent the mean and standard error from three independent experiments (three samples of each). c.p.m. = counts per minute.

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Fig. 4 Immunoblotting detection of type-I collagen (A) and type-III collagen (B) in osteoblast-like cells. The confluent cells were untreated (C) or were treated with 0.05 per cent titanium particles (T) for seventy-two hours. The culture medium was harvested, and the particles were removed. An aliquot of each sample (culture medium) was analyzed by immunoblotting as has been described. The bands of a1(I), a2(I), and a1(III), molecular weight in kilodaltons, as well as 1:2 serial dilutions (D1, D2, and D3) of the samples are shown. These results represent the findings of four independent experiments.

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Fig. 5 Graph showing the effect of small titanium particles on the incorporation of ³H-thymidine in osteoblast-like cells. The confluent cells were incubated with or without small titanium particles for forty-eight and seventy-two hours in the presence of ³H-thymidine (five microcuries per milliliter) for the final eight hours. The radioactivity incorporated into the nuclei of cells was determined by scintillation counting. The mean and the standard error of six to eight samples are shown. With the numbers available, there was no significant difference between the results for the control samples and those for the treated samples. c.p.m. = counts per minute.

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

Particles

Commercially pure titanium particles were purchased from Johnson Matthey (Danvers, Massachusetts). On the average, 27 per cent of these particles were smaller than one micrometer and 91 per cent were smaller than three micrometers^6,9. On the basis of the size distribution of these titanium particles, a 0.1 per cent titanium suspension (volume per volume) contained approximately 4.5 x 10⁷ particles per milliliter. For comparative experiments, silver particles (0.7 to 1.3 micrometers) and large titanium particles (twenty-one to eighty-five micrometers) were also obtained from Johnson Matthey. Monodisperse polystyrene particles, both small (1.14 ± 0.007 micrometers) and large (21.1 ± 4.09 micrometers), were purchased from Polyscience (Washington, Pennsylvania). The particles were sterilized by irradiation with 2.2 megarad (22,000 gray) from a cesium-137 source (model 143; J. L. Sheppherd Irradiator, San Fernando, California) and stored in sterile phosphate-buffered saline solution (pH 7.2). Endotoxin contamination of particles was excluded by limulus assay (E-Toxate; Sigma Chemical, St. Louis, Missouri)⁶.

Cells and Cell Cultures

Human osteoblast-like cell lines MG-63 and HOS (human osteogenic sarcoma) (American Type Culture Collection, Rockville, Maryland) were cultured in monolayer in Dulbecco modified Eagle medium (Gibco, Grand Island, New York) containing 10 per cent fetal bovine serum (Hyclone Laboratories, Logan, Utah) and in a humidified atmosphere of 95 per cent air and 5 per cent carbon dioxide at 37 degrees Celsius.

Treatment of Cells with Particles and Collection of Samples

Confluent cultures of cells were subjected to serum deprivation for twenty-four hours. The culture medium was replaced with serum-free medium containing particles for various time-periods. The tissue-culture medium was collected, centrifuged, and filtered through a 0.22-micrometer polycarbonate filter (Spin-x; Costar, Cambridge, Massachusetts) to remove cell debris and particles. The cell layers were used for RNA isolation, as will be described, or lysed in lysis buffer (fifty-millimolar Tris-hydrochloric buffer, pH 6.8; 0.1 per cent sodium dodecyl sulfate; and five-millimolar EDTA). Cell lysates were cleared by centrifugation and filtration, as has been described.

Extraction of RNA

Total RNA was extracted from the cultured cells with a modification³⁴ of the method of Chomczynski and Sacchi². Monolayer cultures were washed twice with cold phosphate-buffered saline solution and lysed in four-molar guanidine isothiocyanate. An equal volume of phenol (pH 7.4) was then added to the cell lysate. The mixture was centrifuged at 10,000 times gravity for twenty minutes at 40 degrees Celsius, and the aqueous phase containing the RNA was transferred to a new tube and purified by repeated precipitation with 70 per cent ethanol. The yield of total RNA was approximately the same in each sample, and it depended on the number of cells and not the experimental conditions.

Northern Blot Hybridization

Steady-state levels of mRNA were determined with Northern blot hybridization analysis. Approximately ten micrograms of total RNA was denatured in 50 per cent formamide, 17.5 per cent formaldehyde, and MOPS buffer (twenty-millimolar 3-[N-morpholino]propanesulfonic acid at pH 7.0, five-millimolar sodium acetate, and one-millimolar EDTA). The solution was subjected to electrophoresis in a 1 per cent agarose gel and transferred to GeneScreen Plus membranes (New England Nuclear, Boston, Massachusetts). Blots were hybridized with radioactively labeled specific cDNA (complementary DNA) probes at a concentration of 3 x 10⁶ counts per minute per milliliter (2 to 6 x 10⁸ counts per minute per microgram of cDNA). The cDNA probes were labeled with ³²P-deoxycytidine triphosphate³⁴. The recombinant plasmid DNAs used as cDNA probes were a 1.8-kilobase-long cDNA probe for human collagen a₁(I) Hf677 and a 1.3-kilobase-long cDNA probe for human collagen a₁(III) Hf934. After hybridization, the blots were washed and exposed to Kodak XAR-5 film (Eastman Kodak, Rochester, New York) at -70 degrees Celsius.

Metabolic Labeling and Assessment of Total Collagen Synthesis

Confluent cell cultures in ten-centimeter dishes were serum-deprived for twenty-four hours. The cultures were incubated with fresh serum-free medium supplemented with fifty micrograms of ascorbic acid per milliliter and fifty micrograms of ß-aminopropionitrile per milliliter for twenty-four hours with or without small titanium particles at a concentration of 0.05 per cent (volume per volume). The cells were then labeled with twenty-five microcuries of L-[2,3,4,5-³H]proline (Amersham, Arlington Heights, Illinois) per milliliter (specific activity, eighty-one curies per mole) in the same medium for an additional forty-eight hours. The medium and cells were collected separately. The medium was filtered through a 0.22-micrometer filter to remove particles. Cells were lysed and sonicated in lysis buffer, and particles were removed by filtering the solution through a 0.22-micrometer filter. Total collagen synthesis was determined by measuring total protein concentrations of the medium and the cell lysates with use of the bicinchoninic acid method (Pierce, Rockford, Illinois). Non-collagenous proteins were digested, and collagens were solubilized by pepsin digestion⁴. Aliquots of samples containing 120 micrograms of total protein were mixed with pepsin (a protein-to-pepsin ratio of 6:1) at 100 micrograms per milliliter and dialyzed for twenty-four hours against 0.5-molar acetic acid followed by an overnight dialysis against ten-millimolar ammonium bicarbonate and two-millimolar phenylmethylsulfonyl fluoride at 4 degrees Celsius⁴. Samples were lyophilized and redissolved in an aliquot of lysis buffer. The trichloroacetic acid precipitable radioactivities were determined in aliquots of the samples with use of a scintillation counter (model 3800; Beckman Instruments, Fullerton, California).

Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis and Western Blot Technique

Aliquots of non-radioactive medium and samples of cell lysate were fractionated in 5 per cent sodium dodecyl sulfate polyacrylamide gel electrophoresis under reducing conditions. Samples were transferred onto a nitrocellulose membrane (Bio-Rad Laboratories, Richmond, California)³, blocked for two hours at room temperature, and incubated with specific antisera for two hours. Polyclonal antibody against human type-I collagen (a gift from Dr. J. Mollenhauer, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois) and monoclonal antibody to human type-III collagen (Accurate Chemical and Scientific, Westbury, New York) were used in the present study. The first antibodies were detected by peroxidase-labeled second antibodies (Accurate Chemical and Scientific) and visualized with an enhanced chemiluminescence system (Amersham)³.

Determination of Viability and Proliferation of Cells

Confluent cell cultures were serum-deprived for twenty-four hours, and the medium was then replaced with serum-free Dulbecco modified Eagle medium with or without titanium particles at various concentrations for various periods. The cell viability was determined with trypan-blue exclusion⁷. At least 300 cells from each particle treatment were counted. The cytoplasmic staining of trypan blue in dead cells did not interfere with the distinguishing of phagocytosed particles. Cell proliferation was determined by incorporation of ³H-thymidine with a microplate assay system²⁸.

Analysis of Data

The Student t test with Bonferroni correction was used for statistical analysis of quantitative data.

Results

Introduction | Materials and Methods | Results | Discussion | References

Steady-State mRNA Levels of Collagen in Osteoblast-Like Cells

Untreated MG-63 cells expressed high levels of mRNA for procollagen a₁(I) and a₁(III). These mRNA levels decreased in a dose-dependent manner when the cells were treated with titanium particles (Fig. 1, A). The suppressive effect of titanium particles on the level of collagen mRNA lasted throughout a seventy-two-hour treatment period, although treatment for forty-eight hours appeared to have the strongest effect (Fig. 1, B). A strong suppression of the mRNA levels of procollagen a₁(I) and a₁(III) was also observed in human osteogenic sarcoma cells treated with small titanium particles compared with that of the untreated controls.

All particles that were smaller than three micrometers, regardless of composition and including both titanium and polystyrene, decreased the mRNA levels of procollagen a₁(I) and a₁(III) (Fig. 2, A; lanes 2, 4, and 6), but large particles (more than twenty micrometers) did not (Fig. 2, A; lanes 3 and 5). Thus, the suppression of collagen mRNAs in osteoblast-like cells was related to the size but not to the composition of the particles. Medium that had been preincubated for forty-eight hours with titanium particles without cells had no effect on the expression of the collagen genes compared with that of the untreated controls (Fig. 2, B). This finding excluded the possibility that titanium ions or particle contaminants were responsible for the suppression of the levels of collagen mRNA.

Collagen Synthesis in Osteoblast-Like Cells

Total collagen synthesis in MG-63 cells treated with titanium particles was decreased by 46 per cent in culture medium (p < 0.05) and by 68 per cent in cell lysates (p < 0.05) compared with that of the untreated controls (Fig. 3). As shown by the Western blot technique, the synthesis of both type-I and type-III collagen was significantly decreased (p < 0.05) in MG-63 cells treated with titanium particles (Fig. 4, A and B). The 2:1 ratio between a₁(I) and a₂(I) chains of type-I collagen remained unchanged in both the cells treated with titanium particles and the untreated controls (Fig. 4).

Viability and Proliferation of Cells

The viability of MG-63 cells was not affected by treatment with titanium particles. The percentage of viable cells exposed to titanium particles did not change, and more than 92 per cent of cells in both the treated and the untreated groups remained alive during a period of seventy-two hours. The challenge of MG-63 cells with small titanium particles during a seventy-two-hour period had no effect on the incorporation of ³H-thymidine compared with that of the untreated controls (Fig. 5). Therefore, treatment with titanium particles had no effect on the viability and proliferation of MG-63 cells. Most importantly, MG-63 cells were capable of phagocytosis as shown by confocal microscopy. Particles were observed in the cytoplasm of every cell treated with small titanium particles, but not those treated with large particles, while the cell remained alive, resisting the penetration of trypan blue.

Discussion

Introduction | Materials and Methods | Results | Discussion | References

Aseptic loosening and focal osteolysis with or without loosening are the most frequent complications of total joint replacement. Although the pathogenesis of these related processes has yet to be elucidated fully, it is increasingly recognized that the interaction between particles of wear debris and cells in the periprosthetic milieu is a critical element^9,12,29.

Other investigators have suggested that the interfacial membrane may provide access for wear debris to enter the periprosthetic space^22,27, where the particles then may interact directly with osteoblasts. However, little information has been reported about the effect of debris on osteoblast function. The present study demonstrates that the expression of the genes that code for procollagen a₁(I) and a₁(III) is markedly decreased in response to particles in osteoblast-like cells and that this leads to a decrease in the biosynthesis of type-I and type-III collagen. The suppression of the genes that code for the expression of these collagens in osteoblast-like cells was associated with the size, but not the composition, of the particles. This finding is in contrast to observations of macrophages^12,24,28,30 and fibroblasts^22,33,34, in which the response is related to the composition of the particles.

Human osteogenic cell-line MG-63 is an excellent cell line for studying osteoblast function, as these cells maintain the characteristics of osteoblasts, including 1,25-dihydroxyvitamin D₃-induced synthesis of collagen, production of alkaline phosphatase and osteocalcin, and parathyroid hormone-stimulated production of cyclic adenosine monophosphate^1,4,18,20. The finding that the osteoblast cell-line HOS (human osteogenic sarcoma) also exhibited suppression of the procollagen gene in response to titanium particles demonstrates that this phenomenon is not limited to one cell line.

In order to reproduce in vivo conditions as closely as possible, small titanium particles, which are representative of those in periprosthetic tissues^5,15,31, were used. Large titanium particles (more than twenty micrometers) and other metallic (silver) and polymeric (polystyrene) particles of various sizes were also used. All small particles, but not large particles, suppressed the genes that code for the expression of collagen in the MG-63 cells. In the present study, we also showed that the MG-63 cells are capable of phagocytosis of the small particles. Furthermore, other experiments done by us have revealed that cytochalasin B, which inhibits phagocytosis by affecting actin assembly²⁵, diminishes the titanium-particle-induced suppression of the genes that code for the expression of collagen in MG-63 cells. This finding suggests that phagocytosis of particles by these osteoblast-like cells is required in order to produce this suppressive effect on gene expression. Because particle-free medium from particles that had been incubated in the absence of cells had no effect on the expression of genes, the possibility that the suppression of genes and the reduced biosynthesis of collagen were mediated by titanium ions or soluble contaminants on the surface of the particles was excluded.

Net bone formation is the result of a dynamic balance between bone resorption and bone formation. To date, most in vitro studies have focused on bone resorption and have demonstrated that particles of phagocytosable size provoke macrophages to produce various cytokines, which then stimulate osteoclastic bone resorption^6,8,30. Moreover, Goodman et al. showed that small polyethylene and cobalt-chromium-alloy particles not only increased the number of osteoclasts but also reduced the net bone formation in a bone-harvest chamber in vivo¹⁰. As far as we know, ours is the first study to indicate that decreased bone formation may result directly from suppressed osteoblast function and the reduced biosynthesis of bone collagen in response to particles of wear debris. These findings may have important implications with regard to the pathogenesis of periprosthetic osteolysis.

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Introduction | Materials and Methods | Results | Discussion | References

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Turner, T. M.; Urban, R. M.; Sumner, D. R.; and |and |Galante, J. O.: Revision, without cement, of aseptically loose, cemented total hip prostheses. Quantitative comparison of the effects of four types of medullary treatment on bone ingrowth in a canine model. J. Bone and Joint Surg.,75-A: 845-862, June 1993.75-A845 1993

Yao, J.; Glant, T. T.; Hutchinson, N.; and |and |Kuettner, K. E.: Gene regulation of collagenase, stromelysin, TIMP and collagens in synovial fibroblasts exposed to titanium particulates. Trans. Orthop. Res. Soc.,19: 260, 1994.19260 1994

Yao, J.; Glant, T. T.; Lark, M. W.; Mikecz, K.; Jacobs, J. J.; Hutchinson, N. I.; Hoerrner, L. A.; Kuettner, K. E.; and |and |Galante, J. O.: The potential role of fibroblasts in periprosthetic osteolysis: fibroblast response to titanium particulates. J. Bone and Miner. Res.,10: 1417-1427, 1995.101417 1995 [CrossRef]

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Maloney, W. J.; Jasty, M.; Rosenberg, A.; and |and |Harris, W. H.: Bone lysis in well-fixed cemented femoral components. J. Bone and Joint Surg.,72-B(6): 966-970, 1990.72-B(6)966 1990

Murray, D. W., and |and |Rushton, N.: Macrophages stimulate bone resorption when they phagocytose particles. J. Bone and Joint Surg.,72-B(6): 988-992, 1990.72-B(6)988 1990

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JIANLING YAO, GABRIELLA CS-SZABÓ, JOSHUA J. JACOBS, KLAUS E. KUETTNER, TIBOR T. GLANT; Suppression of Osteoblast Function by Titanium Particles*†. The Journal of Bone & Joint Surgery. 1997 Jan;79(1):107-12.

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