2. Academic Validation
  3. Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification

Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification

  • J Extracell Vesicles. 2024 Apr;13(4):e12425. doi: 10.1002/jev2.12425.
Jianfei Yan 1,  Bo Gao 2,  Chenyu Wang 3,  Weicheng Lu 1,  Wenpin Qin 1,  Xiaoxiao Han 1,  Yingying Liu 4,  Tao Li 5,  Zhenxing Guo 1,  Tao Ye 3,  Qianqian Wan 3,  Haoqing Xu 1 6,  Junjun Kang 4,  Naining Lu 4,  Changhe Gao 1,  Zixuan Qin 3,  Chi Yang 7,  Jisi Zheng 7,  Pei Shen 7,  Lina Niu 3,  Weiguo Zou 8,  Kai Jiao 1
Affiliations

Affiliations

  • 1 Department of Stomatology, Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2 Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 3 State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 4 Department of Neurobiology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 5 Center for Spintronics and Quantum Systems, State Key Laboratory for Mechanical Behavior of Materials, Department of Materials Science and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 6 College of Life Science Northwest University, Xi'an, Shaanxi, China.
  • 7 Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, and National Clinical Research Center of Stomatology, Shanghai, China.
  • 8 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
PMID: 38594791 DOI: 10.1002/jev2.12425
Abstract

Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single-cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV-releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.

Keywords

calcified apoptotic vesicles; extracellular matrix; heterotopic ossification; macrophage polarization; osteogenic microenvironment.

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