The central role of wear debris in periprosthetic osteolysis

Abstract

Periprosthetic osteolysis remains the leading complication of total hip arthroplasty, often resulting in aseptic loosening of the implant, and a requirement for revision surgery. Wear-generated particular debris is the main cause of initiating this destructive process. The purpose of this article is to review recent advances in our understanding of how wear debris causes osteolysis, and emergent strategies for the avoidance and treatment of this disease. The most important cellular target for wear debris is the macrophage, which responds to particle challenge in two distinct ways, both of which contribute to increased bone resorption. First, it is well known that wear debris activates proinflammatory signaling, which leads to increased osteoclast recruitment and activation. More recently, it has been established that wear also inhibits the protective actions of antiosteoclastogenic cytokines such as interferon gamma, thus promoting differentiation of macrophages to bone-resorbing osteoclasts. Osteoblasts, fibroblasts, and possibly lymphocytes may also be involved in responses to wear. At a molecular level, wear particles activate MAP kinase cascades, NFkappaB and other transcription factors, and induce expression of suppressors of cytokine signaling. Strategies to reduce osteolysis by choosing bearing surface materials with reduced wear properties (such as metal-on-metal) should be balanced by awareness that reducing particle size may increase biological activity. Finally, although therapeutic agents against proinflammatory mediators [such as tumor necrosis factor (TNF)] and osteoclasts (bisphosphonates and molecules blocking RANKL signaling) have shown promise in animal models, no approved treatments are yet available to osteolysis patients. Considerable efforts are underway to develop such therapies, and to identify novel targets for therapeutic intervention.

Fig. 1

Cellular and molecular regulation of osteoclastogenesis and the influence of wear debris. Osteoclast precursor cells (OCP) are recruited to the periprosthetic tissues and differentiate into functional osteoclasts (OC), which resorb bone by generation of a resorption pit into which enzymes such as Cathepsin K, tartrate-resistant acid phosphatase (TRAP), and carbonic anhydrase II (CAII) are secreted. Osteoclast maturation and activation is mediated by interaction of RANKL (which can also exist as a cell surface signaling molecule; not shown for clarity) with the OCP receptor RANK. Osteoprotegerin (OPG), a soluble decoy receptor for RANKL, inhibits this pathway, as does the T lymphocyte cytokine, interferon (IFN) gamma. Various other cell types, including macrophages, fibroblasts, and osteoblasts, can modulate this pathway via production of chemokines and proinflammatory cytokines, and can also contribute directly to tissue destruction and/or formation through expression of proteases and collagens. Positive (+) and negative (−) effects of wear particles on key aspects of this complex regulatory system are shown, as are important steps where possible particles involvement has yet to be established (?)