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

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.