Background: Previous studies of bone resorption around failed joint
replacements have focused on a limited number of cytokines, primarily tumor
necrosis factor-a (TNF-a), 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-?-inducible
protein of 10 kDa (IP-10) and monokine induced by interferon-? (MIG),
both chemoattractants of activated Th1 lymphocytes, were also detected.
Soluble intercellular adhesion molecule (sICAM) and transforming growth
factor-ß1 (TGF-ß1) were not detected universally, nor
were TNF-a or IL-1. After a twenty-four-hour organ culture, IL-1ß
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
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-ß1 and sICAM may represent a systemic attempt to
modulate the inflammation. TNF-a 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.