Calreticulin-driven immunogenic cell death promotes osteoclast differentiation and osteoarthritis progression via the LRP1/Rac1 signaling.

Aberrant osteoclast activation in subchondral bone is a hallmark of osteoarthritis (OA). This study identifies calreticulin (CALR), a key immunogenic cell death (ICD) marker, as a critical regulator of osteoclast differentiation and OA pathogenesis. Proteomic analysis revealed elevated CALR expression in subchondral bone from OA patients, which was further validated in human specimens and a destabilization of the medial meniscus (DMM)-induced murine OA model. In vitro, CALR upregulation during osteoclast differentiation activated the low-density lipoprotein receptor-related protein 1 (LRP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling pathway, promoting osteoclastogenesis and bone resorption. These effects were suppressed by the apoptosis inhibitor zVAD-fmk or CALR knockdown. CALR-deficient mice exhibited attenuated subchondral bone damage and delayed OA progression post-DMM. Mechanistically, CALR governs osteoclast function via LRP1/Rac1-mediated nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) activation and secretion of bone-resorbing factors (matrix metalloproteinase-9 (MMP-9), cathepsin K (CTSK)). Our study establishes CALR as a novel therapeutic target for OA, bridging ICD to osteoclast-driven subchondral bone resorption and microarchitectural disruption.