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Stage-specific and location-specific cartilage calcification in osteoarthritis development
  1. Xiaozhao Wang1,2,3,4,
  2. Qin Wu3,
  3. Ru Zhang1,2,3,4,
  4. Zhang Fan3,
  5. Wenyue Li1,2,3,4,
  6. Renwei Mao5,
  7. Zihao Du5,
  8. Xudong Yao6,
  9. Yuanzhu Ma1,2,3,4,
  10. Yiyang Yan1,2,3,4,
  11. Wei Sun1,2,3,4,
  12. Hongwei Wu1,2,3,4,
  13. Wei Wei6,
  14. Yejun Hu1,4,
  15. Yi Hong1,2,3,4,
  16. Huan Hu5,
  17. Yi Wen Koh3,
  18. Wangping Duan7,
  19. Xiao Chen1,2,3,4,
  20. Hongwei Ouyang1,2,3,4
  1. 1Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  2. 2Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  3. 3Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  4. 4China Orthopedic Regenerative Medicine Group, CORMed, Hangzhou, Zhejiang, China
  5. 5ZJU-UIUC Institute, International Campus, Zhejiang University, Haining, Zhejiang, China
  6. 6International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
  7. 7Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
  1. Correspondence to Professor Hongwei Ouyang, 1. Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 2. Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China. 3. Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China. 4. China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China., Zhejiang University, Hangzhou, Zhejiang, China; hwoy{at}zju.edu.cn

Abstract

Objectives This study investigated the stage-specific and location-specific deposition and characteristics of minerals in human osteoarthritis (OA) cartilages via multiple nano-analytical technologies.

Methods Normal and OA cartilages were serially sectioned for micro-CT, scanning electron microscopy with energy dispersive X-ray spectroscopy, micro-Raman spectroscopy, focused ion beam scanning electron microscopy, high-resolution electron energy loss spectrometry with transmission electron microscopy, nanoindentation and atomic force microscopy to analyse the structural, compositional and mechanical properties of cartilage in OA progression.

Results We found that OA progressed by both top-down calcification at the joint surface and bottom-up calcification at the osteochondral interface. The top-down calcification process started with spherical mineral particle formation in the joint surface during early-stage OA (OA-E), followed by fibre formation and densely packed material transformation deep into the cartilage during advanced-stage OA (OA-A). The bottom-up calcification in OA-E started when an excessive layer of calcified tissue formed above the original calcified cartilage, exhibiting a calcified sandwich structure. Over time, the original and upper layers of calcified cartilage fused, which thickened the calcified cartilage region and disrupted the cartilage structure. During OA-E, the calcified cartilage was hypermineralised, containing stiffer carbonated hydroxyapatite (HAp). During OA-A, it was hypomineralised and contained softer HAp. This discrepancy may be attributed to matrix vesicle nucleation during OA-E and carbonate cores during OA-A.

Conclusions This work refines our current understanding of the mechanism underlying OA progression and provides the foothold for potential therapeutic targeting strategies once the location-specific cartilage calcification features in OA are established.

  • osteoarthritis
  • osteoarthritis, Knee
  • crystal arthropathies

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors XW, QW and RZ contributed equally for this work. XW and HO conceived the project; XW, QW, ZF, WL, ZD and RM carried out the experiments; ZF and RZ performed the 3D rendering of FIB-SEM; QW, ZF and YY performed the histological staining and nanoindentation test; YH analysed the mechanical response; XW and HO wrote the manuscript; all authors reviewed and edited on the manuscript. HO accepted full responsibility for the finished work, had access to the data and controlled the decision to publish.

  • Funding This work was supported by the National Science Foundation of China (T2121004, 31830029, 82002271, 81902187).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.