John C. Clohisy, M.D.

DEPARTMENT OF Orthopaedic Surgery
Keywords: implant particles, osteolysis, TNF, osteoclastogenesis, NF-kB

The overall focus of our research effort is to investigate the cellular and molecular mechanisms that mediate implant particle-induced bone resorption. Aseptic loosening remains the major problem that limits the survivorship of total joint replacement implants. Prosthetic loosening results from osteolysis around the implant that is stimulated by particulate debris generated from the joint replacement interfaces. A chronic inflammatory reaction in response to wear particles results in secretion of various proinflammatory cytokines that mediate localized implant-associated osteolysis.

The specific role of each proinflammatory mediator in particle-induced osteolysis remains unclear, yet TNF has emerged as the cytokine playing a fundamental role in this pathologic response. This potent osteoclastogenic factor is known to activate NF-kB, an inducible transcription complex essential for osteoclastogenesis. We have demonstrated that in osteoclast precursor cells, implant debris activates NF-kB via a TNF-dependent mechanism.

Additionally, genetic blockade of TNF signaling, utilizing a TNF receptor knockout mouse, prevents experimental particle-induced osteolysis. These findings suggest that implant particles stimulate osteolysis via a mechanism in which TNF activation of NF-kB plays a pivotal role. Thus, our present effort is targeted at understanding the specific molecular events by which wear particles activate NF-kB and prompt osteoclastogenesis. The long-term goal of this work is to identify novel targets for therapeutic intervention and inhibition of particle-induced osteolysis.