Inhibition of Sclerostin Protected Against Particle-Induced Osteolysis via Activation of Wnt Signaling and Suppression of Osteoclast Function.

Abstract

Periprosthetic osteolysis induced by wear debris remains a leading cause of aseptic loosening after joint arthroplasty, with no established pharmacological treatment. We investigated an anti-sclerostin antibody (Ab-Scl) and elucidated its mechanism of action in cobalt-chromium (CoCr) particle-induced osteolysis. Tartrate-resistant acid phosphatase (TRAP)-tdTomato mice with labeled mature osteoclasts (mOCs) were used. CoCr particles were applied to the calvarial bone, with or without Ab-Scl administration. Intravital two-photon bone imaging, microcomputed tomography (μCT), and histological and immunohistochemical analyses were performed to evaluate osteolysis, osteoclast activity, and β-catenin expression. In vitro assays using RAW264.7-derived osteoclast-like cells were conducted to investigate downstream signaling pathways. μCT analysis revealed that CoCr particles reduced the bone volume-to-tissue volume fraction and trabecular thickness while increasing trabecular separation and the structural model index; conversely, Ab-Scl significantly attenuated osteolytic changes. Histological analysis showed that CoCr exposure increased the eroded surface area and number of TRAP-positive osteoclasts, both of which were significantly decreased by Ab-Scl. Immunohistochemistry demonstrated that CoCr exposure suppressed β-catenin expression on the bone surface, which was restored by Ab-Scl. Intravital two-photon microscopy revealed that CoCr particles reduced mOC motility and increased the acidic resorptive area, whereas Ab-Scl reversed these changes, enhancing motility and suppressing bone resorption. In vitro, RSPO2 enhanced osteoclastic bone resorption, pit formation, and Pyk2 phosphorylation, which were suppressed by PF-562271. Ab-Scl modulated osteoclast function through Wnt/β-catenin-related mechanisms, potentially involving Pyk2-related pathways, thereby suppressing CoCr particle-induced osteolysis. These findings suggest that Ab-Scl is a promising pharmacological strategy for preventing aseptic loosening following joint arthroplasty.