The Journal of Bone and Joint Surgery (American). 2007;89:1081-1089.
doi:10.2106/JBJS.F.00330
© 2007 The Journal of Bone and Joint Surgery, Inc.
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Assessing Osteolysis with Use of High-Throughput Protein Chips

Arun S. Shanbhag, PhD, MBA1, Adam M. Kaufman, MD1, Koichiro Hayata, MD1 and Harry E. Rubash, MD1

1 Biomaterials Laboratory, Massachusetts General Hospital, GRJ 1115, 55 Fruit Street, Boston, MA 02114. E-mail address for A.S. Shanbhag: shanbhag{at}helix.mgh.harvard.edu

Investigation performed at the Biomaterials Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Zimmer, Inc. Neither they nor a member of their immediate families received 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, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Background: Previous studies of bone resorption around failed joint replacements have focused on a limited number of cytokines, primarily tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin (IL)-1, and IL-6, with use of enzyme-linked immunosorbent assay and immunohistochemistry techniques. In this study, we utilized high-throughput protein chips to profile twenty-nine inflammatory cytokines around failed total joint replacements.

Methods: Peri-implant granulomatous tissues were harvested from around the failed total hip prostheses of thirteen patients. Synovial lining capsular tissues from thirteen patients with end-stage degenerative joint disease were used as controls. After homogenization, twenty-nine cytokines were quantified with use of high-throughput protein chips.

Results: IL-6 and IL-8 were found consistently in failed joint replacement tissues, reaffirming their prominent role in osteoclastogenesis and end-stage bone resorption. High levels of interferon-{gamma}-inducible protein of 10 kDa (IP-10) and monokine induced by interferon-{gamma} (MIG), both chemoattractants of activated Th1 lymphocytes, were also detected. Soluble intercellular adhesion molecule (sICAM) and transforming growth factor-beta1 (TGF-beta1) were not detected universally, nor were TNF-{alpha} or IL-1. After a twenty-four-hour organ culture, IL-1beta levels increased substantially along with those of other mediators. We measured but did not detect any activators of cytotoxic T-cells, antibody-producing Bcells, or eosinophils involved in delayed-type hypersensitivity. Variations from patient to patient were seen across all cytokines and highlight the unique response of individual patients to their joint replacements.

Conclusions: In failed total joint replacements in patients with end-stage osteolysis, IL-6 and IL-8 may be the primary drivers of osteoclastogenesis. The presence of IP-10 and MIG imply a role for T-cells, while TGF-beta1 and sICAM may represent a systemic attempt to modulate the inflammation. TNF-{alpha} and IL-1 do not appear to play a major role in the end stages of the disease.

Clinical Relevance: These results demonstrate that proteomic tools can provide a foundation for understanding the cytokine-driven osteolysis cascade and a base from which to identify and evaluate potential targets for blockage or augmentation.


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