Anti-RANKL antibody treatment mitigates subchondral bone loss and cartilage degeneration without affecting synovial inflammation in a mouse model of rotator cuff tear arthropathy.

Aims: Enhanced osteoclast activity in subchondral bone is implicated in osteoarthritis (OA) progression, but the contribution of osteoclasts versus synovial inflammation in cuff tear arthropathy (CTA) remains unclear. This study investigated whether inhibition of osteoclasts using an anti-receptor activator of nuclear factor κB ligand (RANKL) antibody can suppress joint degeneration in a mouse CTA model without affecting synovial inflammation. Methods: A modified CTA (mCTA) model was established in mice by resecting the supraspinatus and infraspinatus tendons, the superior joint capsule, and the long head of the biceps tendon in the right shoulder of C57BL/6J mice. Mice were assigned to four groups: sham or mCTA, each treated with phosphate-buffered saline or anti-RANKL antibody (5 mg/kg subcutaneously every two weeks). Four weeks post-surgery, histological analyses of the humeral head were performed using the Murine Shoulder Arthritis Score (MSAS), immunohistochemistry for osteoclasts, osteoblasts, RANKL/osteoprotegerin (OPG), inflammatory cytokines, and catabolic enzymes, and quantification of synovial M1 macrophages. Subchondral bone volume (BV) was assessed via the bone volume/tissue volume ratio. Results: The mouse mCTA model reproduced clinically relevant CTA phenotypes, including cartilage degeneration, subchondral bone loss, and joint surface collapse, within four weeks. RANKL expression and osteoclast surface increased in the superior and middle zones, while osteoblasts decreased. Synovial RANKL expression was low and unchanged after mCTA surgery. Anti-RANKL antibody administration significantly suppressed osteoclast surface and preserved subchondral BV, leading to attenuation of cartilage degeneration and reduced expression of inflammatory cytokines and catabolic enzymes in cartilage and subchondral bone. The synovitis score, synovial M1 macrophages, and inflammatory factors were unaffected, indicating that suppression of osteoclasts was sufficient to mitigate joint degeneration. Conclusion: Inhibition of subchondral osteoclasts via anti-RANKL antibody reduces CTA-associated cartilage and bone degeneration without altering synovitis. These findings suggest that targeting osteoclasts may represent a promising disease-modifying strategy for CTA, and targeting RANKL with denosumab may prevent or slow shoulder OA progression.