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

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

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: jqunhua@163.com.
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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