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Updated: Sep 13, 2025

Differentiation of Functional Osteoclasts from Human Peripheral Blood CD14+ Monocytes
Published on: January 27, 2023
Calreticulin-driven immunogenic cell death promotes osteoclast differentiation and osteoarthritis progression via the
Qi Ma1, Zhibin Lan1, Yang Yang1
1The Third Ward of Orthopaedic Department, Institute of Osteoarthropathy, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, PR China; Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, PR China.
Abstract:
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.
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