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Wear Debris Inhibition of Anti-Osteoclastogenic Signaling by Interleukin-6 and Interferon-γMechanistic Insights and Implications for Periprosthetic Osteolysis
Diptendu S. Rakshit, PhD1; Khanh Ly, BS1; Tapas K. Sengupta, PhD2; Bryan J. Nestor, MD1; Thomas P. Sculco, MD1; Lionel B. Ivashkiv, MD1; P. Edward Purdue, PhD1
1 Osteolysis Research Laboratory, The Hospital for Special Surgery, Caspary Building, Room 528, 535 East 70th Street, New York, NY 10021. E-mail address for P.E. Purdue: purduee@hss.edu
2 Philip Morris USA Research Center, 4201 Commerce Road, Richmond, VA 23234
View Disclosures and Other Information
The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Osteolysis Research Laboratory, The Hospital for Special Surgery, New York, NY

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Apr 01;88(4):788-799. doi: 10.2106/JBJS.E.00711
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Abstract

Background: Wear debris challenge of macrophages provokes the generation of proinflammatory cytokines, which contribute to periprosthetic osteolysis. However, it is not known whether this effect is accompanied by reprogramming of other cytokines present within the periprosthetic tissue that may be involved in anti-osteoclastogenic activities. In the present study, we examined the ability of wear debris particles to inhibit the signaling of two such cytokines, interleukin-6 and interferon-?.

Methods: Human osteoclast precursor cells were challenged with particles of titanium or polymethylmethacrylate bone cement prior to the addition of the cytokines interleukin-6 or interferon-?. Interleukin-6 signaling was determined by measuring the activation of STAT3 signal transduction with use of immunoblotting and electrophoretic mobility shift assays. Interferon-? signaling was determined by measuring the activation of STAT1 with use of immunoblotting and electrophoretic mobility shift assays and by measuring the expression of interferon-?-inducible genes with use of real-time reverse transcription-polymerase chain reaction assays. Involvement of mitogen-activated protein kinases in cytokine signaling was assessed by including mitogen-activated protein kinase inhibitors in these assays and also by means of immunoblot assessment of mitogen-activated protein kinase activation by wear debris particles. Wear debris modulation of expression of the cytokine suppressors SOCS1 and SOCS3 (as well as pro-inflammatory mediators) was assessed with use of real-time reverse transcription-polymerase chain reaction assays.

Results: Both titanium and polymethylmethacrylate particles potently inhibited interleukin-6-induced STAT3 activation in human osteoclast precursor cells. Inhibition of p38 mitogen-activated protein kinase, which is activated by titanium and polymethylmethacrylate, reversed the inhibitory effects of these particles on interleukin-6 signaling, whereas inhibition of ERK and JNK mitogen-activated protein kinases (which are also activated by both types of wear debris) had no effect. Titanium and polymethylmethacrylate also both induced expression of SOCS3, an inhibitor of interleukin-6 signaling. In addition to its effects on interleukin-6 signaling, titanium also profoundly inhibited the interferon-?-induced activation of STAT1 and the expression of interferon-?-inducible genes, whereas polymethylmethacrylate had no effect on interferon-? signaling.

Conclusions: Titanium inhibits both interferon-? and interleukin-6 signaling in human osteoclast precursor cells, whereas polymethylmethacrylate bone cement inhibits only the latter. Wear particle inhibition of interleukin-6 specifically involves the activation of p38 mitogen-activated protein kinase and is accompanied by substantial induction of SOCS3, an inhibitor of interleukin-6 signaling. In contrast, titanium inhibition of interferon-? signaling is not dependent on mitogen-activated protein kinase activation and is accompanied by only modest induction of the interferon-? inhibitor SOCS1.

Clinical Relevance: The critical role of wear debris in the development of periprosthetic osteolysis likely involves the inhibition of anti-inflammatory/anti-osteoclastogenic cytokine signaling in addition to the well-established induction of pro-inflammatory mediators. Strategies to augment these "protective" signaling pathways may therefore have therapeutic potential for the treatment of periprosthetic osteolysis.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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