Objective. To investigate the effect of osteoclastogenesis inhibitory factor/osteoprotegerin (OPG) on chondrocytes in the development of osteoarthritis (OA) in vivo.Methods. To determine the role of endogenous OPG in the progression of OA, OA was surgically induced in OPG ؉/؊ mice and their wild-type (WT) littermates. To determine the role of exogenous OPG, knee joints of C57BL/6J mice with surgically induced OA were injected intraarticularly with recombinant human OPG (rHuOPG) or vehicle 5 times a week. All mice were euthanized 4 weeks after OA induction; joints were harvested and evaluated immunohistochemically.Results. Although OA changes were induced in both WT and OPG ؉/؊ mice, the degenerative changes in the articular cartilage were significantly enhanced in OPG ؉/؊ mice. In C57BL/6J mice with surgically induced OA, intraarticular OPG administration protected the articular cartilage from the progression of OA. The Mankin and cartilage destruction scores in OPGtreated animals were ϳ50% of those seen in the control group. Furthermore, OPG administration significantly protected articular cartilage thickness. Findings of the TUNEL assay indicated that rHuOPG prevented chondrocyte apoptosis in joints with surgically induced OA. Results of immunostaining indicated that OPG protein was detected in the synovium and in resident chondrocytes at higher levels in the OPG-treated group than in the control group.Conclusion. These data indicate that endogenous OPG had a protective effect against the cartilage destruction that occurs during OA progression. Furthermore, direct administration of rHuOPG to articular chondrocytes prevented cartilage destruction in an experimental murine model of OA via prevention of chondrocyte apoptosis.

Objective. To investigate the molecular mechanisms underlying particle-induced osteolysis, we focused on osteopontin (OPN), a cytokine and cellattachment protein that is associated with macrophage chemoattractant and osteoclast activation.Methods. We compared OPN protein levels in human periprosthetic osteolysis tissues with those in osteoarthritis (OA) synovial tissues. To investigate the functions of OPN during particle-induced osteolysis in vivo, titanium particles were implanted onto the calvaria of OPN-deficient mice and their wild-type (WT) littermates. Mice were killed on day 10 and evaluated immunohistologically. The effects of OPN deficiency on the secretion of inflammatory cytokines were examined using cultured bone marrow-derived macrophages (BMMs). BMMs from OPN-deficient and WT mice were cultured with titanium particles for 12 hours, and the concentrations of inflammatory cytokines in the conditioned media were measured by enzyme-linked immunosorbent assay.Results. Expression of OPN protein was enhanced in human periprosthetic osteolysis tissues as compared with OA synovial tissues. In the particle-induced model of osteolysis of the calvaria, bone resorption was significantly suppressed by OPN deficiency via inhibition of osteoclastogenesis, whereas an inflammatory reaction was observed regardless of the genotype. Results of immunostaining indicated that OPN protein was highly expressed in the membrane and bone surface at the area of bone resorption in WT mice. When BMMs were exposed to titanium particles, the concentration of proinflammatory cytokines, such as tumor necrosis factor ␣, interleukin-1␣ (IL-1␣), IL-1␤, and IL-6, as well as chemotactic factors, such as monocyte chemoattractant protein 1 and macrophage inflammatory protein 1␣, in the conditioned medium were significantly reduced by OPN deficiency. Whereas phagocytic activity of BMMs was not attenuated by OPN deficiency, phagocytosis-mediated NF-B activation was impaired in OPN-deficient BMMs. These data indicated that OPN was implicated in the development of particleinduced osteolysis via the orchestration of pro-/ antiinflammatory cytokines secreted from macrophages.Conclusion. OPN plays critical roles in wear debris-induced osteolysis, suggesting that OPN is a candidate therapeutic target for periprosthetic osteolysis.

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