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

  • Int Immunopharmacol. 2025 Jul 25:163:115277. doi: 10.1016/j.intimp.2025.115277.
Qi Ma  1 ,  Zhibin Lan  1 ,  Yang Yang  1 ,  Rui Sun  1 ,  Di Xue  2 ,  Xue Lin  2 ,  Yajing Su  2 ,  Long Ma  3 ,  Zhijun Hu  3 ,  Gang Wu  3 ,  Xiaoxin He  3 ,  Kuanmin Tian  3 ,  Qunhua Jin  4
Affiliations
  • 1. The 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.
  • 2. Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, PR China.
  • 3. The 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.
  • 4. The 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. Electronic address: [email protected].
PMID: 40714468 DOI: 10.1016/j.intimp.2025.115277
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.

Keywords
Calreticulin; Immunogenic cell death; Osteoarthritis; Osteoclast differentiation.
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