Loading-Induced Reduction in Sclerostin as a Mechanism of Subchondral Bone Plate Sclerosis in Mouse Knee Joints During Late-Stage Osteoarthritis

Haoruo Jia, Xiaoyuan Ma, Yulong Wei, Wei Tong, Robert J. Tower, Abhishek Chandra, Luqiang Wang, Zeyang Sun, Zhaochun Yang, Farid Badar, Kairui Zhang, Wei Ju Tseng, Ina Kramer, Michaela Kneissel, Yang Xia, X. Sherry Liu, James H.C. Wang, Lin Han, Motomi Enomoto-Iwamoto, Ling Qin

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Objective: To establish an unbiased, 3-dimensional (3-D) approach that quantifies subchondral bone plate (SBP) changes in mouse joints, and to investigate the mechanism that mediates SBP sclerosis at a late stage of osteoarthritis (OA). Methods: A new micro-computed tomography (micro-CT) protocol was developed to characterize the entire thickness of the SBP in the distal femur of a normal mouse knee. Four mouse models of severe joint OA were generated: cartilage-specific Egfr–knockout (Egfr-CKO) mice at 2 months after surgical destabilization of the medial meniscus (DMM), Egfr-CKO mice with aging-related spontaneous OA, wild-type (WT) mice at 10 months after DMM, and WT mice at 14 weeks after DMM plus hemisectomy of the meniscus (DMMH) surgery. As an additional model, mice with knockout of the sclerostin gene (Sost-KO) were subjected to DMMH surgery. Knee joints were examined by micro-CT, histology, and immunohistochemical analyses. Results: Examination of the mouse distal femur by 3-D micro-CT revealed a positive correlation between SBP thickness and the loading status in normal knees. In all 4 mouse models of late-stage OA, SBP sclerosis was restricted to the areas under severely eroded articular cartilage. This was accompanied by elevated bone formation at the bone marrow side of the SBP and a drastic reduction in the levels of sclerostin in osteocytes within the SBP. Unlike in WT mice, no further increase in the thickness of the SBP was observed in response to DMMH in Sost-KO mice. Conclusion: Since focal stress on the SBP underlying sites of cartilage damage increases during late stages of OA, these findings establish mechanical loading–induced attenuation of sclerostin expression and elevation of bone formation along the SBP surface as the major mechanisms characterizing subchondral bone phenotypes associated with severe late-stage OA in mice.

Original languageEnglish (US)
Pages (from-to)230-241
Number of pages12
JournalArthritis and Rheumatology
Volume70
Issue number2
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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