| Wear debris-induced osteolysis is a significant cause of orthopaedic implant failure resulting in the need for revision arthroplasty. Osteolysis is initiated by the phagocytosis of particulate debris and secretion of pro-inflammatory cytokines from macrophages. Tumor necrosis factor-α (TNFα) is critically important in the generation of this inflammatory response and is involved in the differentiation of osteoclasts, which are responsible for the resorption of bone surrounding the prosthetic joint. Osteoclastogenesis is also dependent on receptor activator of NFκB ligand (RANKL), which is expressed on osteoblasts/bone marrow stromal cells and activated T cells. The dominant role of these two cytokines in the osteolytic process makes them excellent pharmacologic targets. Using a variety of in vitro and animal models of osteoclast activity, this research demonstrates that TNFα antagonism (via a soluble TNF receptor fusion protein) blocks cytokine production and osteoclast activity in vitro and prevents bone resorption in vivo with no effect on osteoclast survival. In the absence of an adaptive immune response, adenoviral delivery of a gene encoding a TNF receptor fusion protein resulted in sustained expression of the therapeutic protein and reduction in osteoclast activity. Inhibition of RANKL, completely blocked osteoclastogenesis and osteoclast activity in vivo and was 100-fold more potent than TNFα blockade. A portion of the osteolytic response was found to be T cell-mediated and RANKL-dependent. In an effort to assess the feasibility of RANKL inhibition in humans, possible detrimental effects on homeostatic bone formation and fracture repair were examined and found to be of minimal concern. Overall these experiments provide insight into the etiology of osteolysis, demonstrating that T cells may be involved in the pathogenesis of aseptic loosening and that both TNFα and RANKL, are involved in the inflammatory bone loss associated with particulate wear debris. This work also validates the therapeutic applications of etanercept and RANK:Fc for the treatment of aseptic loosening and indicates that RANK signaling is not absolutely required for normal bone remodeling and fracture healing. |
