JBJS | Oral Pentoxifylline Inhibits Release of Tumor Necrosis Factor-Alpha from Human Peripheral Blood Monocytes : A Potential Treatment for Aseptic Loosening of Total Joint Components

The Journal of Bone & Joint Surgery, Volume 83, Issue 7

Articles | July 01, 2001

Oral Pentoxifylline Inhibits Release of Tumor Necrosis Factor-Alpha from Human Peripheral Blood Monocytes : A Potential Treatment for Aseptic Loosening of Total Joint Components

Paul F. Pollice, MD; Randy N. Rosier, MD, PhD; R. John Looney, MD; J. Edward Puzas, PhD; Edward M. Schwarz, PhD; Regis J. O’Keefe, MD, PhD

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Investigation performed at the University of Rochester Medical Center, Rochester, New York
Paul F. Pollice, MD
Randy N. Rosier, MD, PhD
R. John Looney, MD
J. Edward Puzas, PhD
Edward M. Schwarz, PhD
Regis J. O’Keefe, MD, PhD
Department of Orthopaedics (P.F.P., R.N.R., J.E.P., E.M.S., and R.J.O’K.), Box 665, and Department of Medicine (R.J.L.), University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address for R.J. O’Keefe: regis_okeefe@urmc.rochester.edu

One or more of the authors may receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. Two of the authors hold a United States patent for the use of phosphodiesterase inhibitors to prevent inflammatory bone resorption. There are no current commercial interests and there have been no discussions or relationships with commercial parties concerning this. P.F. Pollice was awarded a 2000 American Orthopaedic Association/Zimmer Resident Travel Award for this work. The work was supported by Public Health Service Awards AR46545 (R.J.O’K.) and AR44220 (R.J.O’K.) from the National Institutes of Health.

The Journal of Bone & Joint Surgery. 2001; 83:1057-1061

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Abstract

Background: Pentoxifylline (Trental) is a methylxanthine-derivative drug that has been used for more than twenty years in the treatment of peripheral vascular disease. Pentoxifylline is also a potent inhibitor of tumor necrosis factor-alpha (TNF-a) secretion, both in vitro and in vivo, and has demonstrated efficacy in the treatment of certain animal and human inflammatory diseases. Pentoxifylline has a potential therapeutic role in the treatment of aseptic loosening of total joint replacement components because it inhibits TNF-a secretion by particle-stimulated human peripheral blood monocytes. The purpose of our study was to determine whether the particle-stimulated secretion of TNF-a by peripheral blood monocytes was inhibited in volunteers who had received pentoxifylline orally.

Methods: Human peripheral blood monocytes were harvested from eight healthy volunteers and were exposed to three different concentrations of titanium particles or to 500 ng/mL of lipopolysaccharide as a positive control. The same volunteers were then given pentoxifylline (400 mg, five times per day) for seven days. Their peripheral blood monocytes were again isolated and exposed to experimental conditions, and the TNF-a levels were measured.

Results: The peripheral blood monocytes from all eight volunteers showed a significant reduction in TNF-a release following oral treatment with pentoxifylline. This reduction was observed at exposures of 10⁷ and 10⁶ titanium particles/mL and in the lipopolysaccharide-treated group, but not at 10⁵ particles/mL.

Conclusions: To our knowledge, this is the first study to demonstrate the ability of an oral drug to decrease the release of TNF-a from human peripheral blood monocytes exposed ex vivo to particle debris. TNF-a is involved in the pathogenesis of osteolysis and subsequent loosening of total joint arthroplasty components. The ability to suppress the release of TNF-a in patients with a total joint replacement may help to control osteolysis and to reduce the development of aseptic loosening. This effect could increase implant longevity and decrease the need for revision arthroplasty.

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Introduction

Introduction | Materials and Methods | Results | Discussion | References

Total joint arthroplasty is usually a successful procedure in the treatment of arthritis. However, osteolysis-related aseptic loosening, which occurs in 20% of patients within ten years after the operation, remains one of the most common and often devastating complications related to arthroplasty and continues to be an important subject of orthopaedic research^1-7. The process of osteolysis has been studied since Charnley et al. first described it more than thirty years ago⁸. Generation of wear debris leads to macrophage activation and to release of cytokines and mediators of inflammation^9-15. Tumor necrosis factor-alpha (TNF-a) plays a central role in the development of particle-induced osteolysis, as indicated by its presence in periprosthetic membranes retrieved from loose implants and its role in inflammation and bone resorption^5,10,14,15. Thus, reducing macrophage secretion of TNF-a in response to wear-debris particles is a biological strategy with potential to control osteolysis.

In vitro studies have shown that TNF-a release by human peripheral blood monocytes can be inhibited by commonly used pharmacological agents. Pentoxifylline has been shown, in vitro, to inhibit the release of TNF-a from human peripheral blood monocytes activated by titanium particles⁹. In an ex vivo study of human peripheral blood monocytes exposed to lipopolysaccharide after harvest from volunteers treated with oral pentoxifylline, Neuner et al. found a significant reduction in the release of TNF-a¹⁶. The purpose of our study was to investigate the ability of pentoxifylline to inhibit titanium-induced release of TNF-a in ex vivo cultures of human peripheral blood monocytes from volunteers treated with the drug. Demonstration of the inhibition of titanium-induced release of TNF-a in this human ex vivo model would warrant consideration of prospective human clinical trials to investigate the ability of pentoxifylline to inhibit osteolysis.

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Fig. 1:: Release of TNF-a, before (Pre-Rx) and after (Post-Rx) oral administration of pentoxifylline, from peripheral blood monocytes stimulated with titanium at concentrations of 10⁷ particles/mL (A), 10⁶ particles/mL (B), or 10⁵ particles/mL (C). The data are presented as the fold increase in the TNF-a release compared with the release from unstimulated peripheral blood monocytes. Each of the eight volunteers are represented by a unique symbol, with the lines joining identical symbols in the pretreatment and posttreatment columns.

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Fig. 2:: The mean percent inhibition, by pentoxifylline, of TNF-a release by peripheral blood monocytes from the eight patients, as determined from the individual data presented in Figure 1, after stimulation with 500 ng/mL of lipopolysaccharide (LPS) or with titanium at concentrations of 10⁷, 10⁶, or 10⁵ particles/mL. The data represent the ratio of the TNF-a released from the peripheral blood monocytes after pentoxifylline treatment divided by the TNF-a released from peripheral blood monocytes before pentoxifylline treatment.

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

Human Volunteers

The institutional review board overseeing human studies at the University of Rochester Medical Center approved the study protocol, and eight healthy subjects gave informed consent to participation. They underwent venipuncture with heparinized syringes, and monocytes were isolated. The volunteers then received pentoxifylline (Trental; Hoechst, Frankfurt, Germany) at an oral dosage of 400 mg five times a day continuously for seven days. After the last dose of pentoxifylline, the volunteers again underwent venipuncture and monocytes were isolated. Three of the volunteers had mild nausea associated with the oral administration of pentoxifylline, but all volunteers completed the study.

Human Peripheral Blood Monocytes

Monocytes from the volunteers were isolated by density-gradient centrifugation prior to and after pentoxifylline treatment^6,9,10. Monocytes were preferentially separated from lymphocytes by adherence to culture plates (Falcon tissue culture dish; Becton Dickinson Labware, Franklin Lakes, New Jersey) for one hour at 37°C and 5% CO2. Lymphocytes were removed by washing the adherent monocytes twice with serum-free RPMI-1640 medium (Gibco, Grand Island, New York). After a fifteen-minute incubation in 3 mL of phosphate-buffered saline solution containing 1mM EDTA and 10% fetal bovine serum (HyClone Labs, Logan, Utah) at 37°C, the monocytes were gently scraped from the flask. The monocytes were then washed twice with sterile phosphate-buffered saline solution, collected by centrifugation, and again suspended in RPMI-1640 medium and 10% fetal bovine serum. Monocyte populations were approximately 95% pure^9,10.

Titanium Particle and Lipopolysaccharide Exposure

The isolated monocytes were plated in twenty-four-well tissue-culture plates at 500,000 cells per well in 1 mL of RPMI-1640 medium containing 10% fetal bovine serum (HyClone Labs). Monocytes from each volunteer were exposed to four different experimental conditions: 10⁷ titanium particles/mL, 10⁶ titanium particles/mL, 10⁵ titanium particles/mL, and 500 ng/mL of lipopolysaccharide (Sigma Chemical, St. Louis, Missouri) within one hour of plating. Titanium particles of 1 to 3 in diameter (Johnson Matthey, Ward Hill, Massachusetts) were washed three times in phosphate-buffered saline solution and were sterilized in an autoclave. Particle suspensions were shown to be free of endotoxins by Limulus assay (BioWhittaker, Walkersville, Maryland). Size analysis was performed with a Coulter ZM Chanelizer (Coulter Electronics, Hialeah, Florida), and >90% of the particles were <5 m in size, as previously described¹⁰. Unexposed controls were also cultured. Each experimental condition was performed four times. The cells were cultured for eighteen hours at 37°C and 5% CO2. Samples were collected, and titanium particles were removed by centrifugation at 4°C. Supernatants were stored at -70°C for TNF-a analysis. The isolations were identically performed both prior to and after oral administration of pentoxifylline.

Assay for TNF-a

Conditioned medium was thawed for TNF-a measurement by ELISA (enzyme-linked immunoabsorbent assay) kits (PharMingen; San Diego, California) consisting of an anti-TNF-detecting antibody bound to the plate followed by a second biotinylated anti-TNF antibody. After the addition of avidin-peroxidase enzyme and 2-(2-methoxyethoxy) ethyl 8-(cis-2-n-octylcyclopropyl) octanoate chromagen (ABTS; Sigma Chemical), the colorimetric change was measured spectrophotometrically at 405 nm (automated MicroElisa plate reader, model MRS 80; Dynex Technologies, Chantilly, Virginia). Optical density was compared with that of standard concentrations of TNF-a, and the concentration was calculated in picograms per milliliter.

Statistical Analysis

The specimens from each of the experimental groups were measured by ELISA in quadruplicate, the results were averaged, and the standard error of the mean was calculated. The concentrations of TNF-a under the experimental conditions—that is, exposure to titanium and lipopolysaccharide—were normalized to the control concentrations for each volunteer. The change in TNF-a release observed after administration of pentoxifylline was then determined for each of the volunteers, under each of the four experimental conditions: 10⁷ titanium particles/mL, 10⁶ titanium particles/mL, 10⁵ titanium particles/mL, and 500 ng/mL of lipopolysaccharide. Comparisons were made by analysis of variance, and significance was assigned for p values of less than 0.05.

Results

Introduction | Materials and Methods | Results | Discussion | References

The mean basal level of TNF-a secretion from peripheral blood monocytes from the eight volunteers was similar before (66.2 ± 15.0 pg/mL) and after (78.5 ± 12.2 pg/mL) the administration of pentoxifylline. When monocytes from each of the eight volunteers were exposed to a low level of titanium (10⁵particles/mL), the TNF-a secretion was not significantly different from the control level (unstimulated monocytes), and the inhibitory effect of pentoxifylline was not significant. TNF-a secretion was greatly decreased, however, after administration of pentoxifylline at particle loads of 10⁷ and 10⁶ titanium particles/mL (Fig. 1).

The mean TNF-a level for the eight volunteers was slightly greater after lipopolysaccharide exposure (686 137 pg/mL) than it was at 10⁷ titanium particles/mL (502 105 pg/mL)—the maximum stimulatory concentration. The results of our study, similar to those described by Neuner et al.¹⁶, showed that pentoxifylline administration significantly inhibited the release of TNF-a from human peripheral blood monocytes exposed to lipopolysaccharide (a 2.19-fold decrease, p = 0.003; Fig. 2). Furthermore, pentoxifylline similarly inhibited the stimulation of TNF-a release by titanium particles: a 52% and 57% inhibition was observed at titanium concentrations of 10⁷ and 10⁶ particles/mL, respectively (p < 0.005 and p < 0.001).

Discussion

Introduction | Materials and Methods | Results | Discussion | References

Aseptic loosening is the most common complication of total joint arthroplasty^1-3,17. Because there is no established method of treatment for this problem, it continues to be a critical area of investigation⁷. A current model explaining the process of aseptic loosening is that wear debris generated from implants is phagocytosed by resident macrophages, leading to their activation and to release of cytokines and other mediators of inflammation^9-15. Of these mediators, TNF-a is believed to be one of the most important in the development of particle-induced osteolysis^5,10,14,15. TNF-a is the earliest proinflammatory mediator released, and its role in osteoclastic bone resorption is well documented^10-12,14,15. It has also been shown that mice genetically deficient in TNF-a-signaling fail to produce an osteolytic response to wear debris¹⁵. Experiments designed to elucidate the cellular pathways involved in TNF-a synthesis demonstrated that pentoxifylline inhibits the release of TNF-a from human peripheral blood monocytes exposed to titanium particles⁹. In subsequent in vivo studies in mice, it was shown that pentoxifylline is as effective at inhibiting particle-induced osteolysis as is the anti-osteoclastic drug alendronate¹⁸.

Pentoxifylline is commonly used pharmacologically for its hemorheologic effects, whereby it increases the deformability of erythrocytes and facilitates blood flow in the setting of peripheral vascular disease¹⁹. However, the effects of pentoxifylline on TNF-a secretion have been related to its activity as an inhibitor of phosphodiesterase, which is an important regulatory molecule in the cyclic-adenosine-monophosphate/protein-kinase-A signaling pathway^19,20. Protein kinase A is present in the cytoplasm as a complex composed of dimeric catalytic subunits and dimeric regulatory subunits^21,22. The binding of cyclic adenosine monophosphate to the regulatory subunits results in release and translocation of the catalytic subunit to the nucleus, where it phosphorylates target proteins and transcription factors^21,22. Thus, increased levels of cyclic adenosine monophosphate activate the protein-kinase-A signaling pathway²². Elevated intracellular cyclic adenosine monophosphate levels can result from either (1) increased synthesis by the enzyme adenylate cyclase or (2) decreased degradation by the enzyme phosphodiesterase^23,24. As a phosphodiesterase inhibitor, pentoxifylline increases intracellular cyclic adenosine monophosphate levels and protein-kinase-A activity^19,20,24.

TNF-a secretion is reduced by activation of the cyclic-adenosine-monophosphate/protein-kinase-A signaling pathway, an effect that has been related to an inhibition in TNF-a gene expression in response to inflammatory stimuli^20,25. The phosphodiesterase inhibitory activity of pentoxifylline has been clearly established, and many in vitro studies have confirmed its role as an inhibitor of TNF-a secretion in response to inflammatory stimuli, including particulate debris^9,25,26. In animal models, pentoxifylline increased survival in the setting of septic shock, and it attenuated the inflammatory responses and improved survival in the setting of acute pancreatitis, fibrotic liver disease, alveolitis, and adjuvant-induced arthritis^19,27-32. Pentoxifylline inhibited particle-mediated bone loss in a murine model, suggesting that this agent may have a role as an inhibitor of periprosthetic bone loss¹⁸. Because of the critical role of TNF-a in producing inflammation, several human clinical trials have been conducted to examine the effect of pentoxifylline in inflammatory diseases^33-40.

The purpose of the present study was to determine whether orally administered pentoxifylline is capable of inhibiting TNF-a secretion by particle-stimulated human peripheral blood monocytes obtained from healthy volunteers. The concentration of pentoxifylline used in the current study (2000 mg/day) was higher than the dose typically given to patients with vascular disease (1200 mg/day). Pentoxifylline has been well tolerated by patients with vascular disease, with a rate of discontinuation due to side effects of only 3.1% in patients treated for as long as sixty weeks⁴¹. However, side effects such as drowsiness, constipation, nausea, and headache have been reported^34,41,42. Three of our volunteers experienced mild nausea that did not require withdrawal from the study. The results of our ex vivo study demonstrate that pentoxifylline has potent anti-inflammatory effects on human peripheral blood monocytes exposed to titanium particles. Specifically, pentoxifylline decreased the release of TNF-a from monocytes exposed to titanium by a mean of 52% and 57% at particle loads of 10⁷ and 10⁶ particles/mL (p < 0.005 and p < 0.001) in this study of eight volunteers. Inhibition was universal at these particle loads.

TNF-a is of central importance in the pathogenesis of aseptic loosening, and the ability to manipulate the release of this proinflammatory cytokine could be an important breakthrough in the treatment of this disease process. The results of our study provide evidence that pentoxifylline may benefit patients with radiographic signs of loosening by inhibiting the release of TNF-a and controlling associated osteolysis. Without data from controlled randomized clinical trials it remains difficult to determine whether pentoxifylline or related pharmacological agents will successfully treat patients with radiographic signs of loosening. The development of loosening is dependent on multiple factors, including patient predisposition, mechanical influences on implants, biological factors, and implant materials and design. Pentoxifylline may inhibit osteolysis at the interface of implants already showing radiographic signs of loosening and may prove to be useful in the treatment of aseptic loosening. Because of the low prevalence of side effects associated with long-term use of pentoxifylline for the treatment of peripheral vascular disease, clinical study of pentoxifylline’s efficacy in the treatment of aseptic loosening seems warranted.

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