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Subchondral bone plate sclerosis during late osteoarthritis is caused by loading-induced reduction in Sclerostin

Jia, Haoruo and Ma, Xiaoyuan and Tong, Wei and Wei, Yulong and Tower, Robert and Chandra, Abhishek and Wang, Luqiang and Sun, Zeyang and Yang, Zhaochun and Badar, Farid and Zhang, Kairui and Tseng, Wei-ju and Kramer, Ina and Kneissel, Michaela and Xia, Yang and Liu, X. Sherry and Wang, James H-C. and Han, Lin and Enomoto-Iwamoto, Motomi and Qin, Ling (2017) Subchondral bone plate sclerosis during late osteoarthritis is caused by loading-induced reduction in Sclerostin. Arthritis and rheumatology.

Abstract

OBJECTIVE:

To establish an unbiased 3D 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).

DESIGN:

A new microCT protocol was developed to characterize the entire SBP thickness in the distal femur of a mouse knee. Four mouse models with severe joint OA were generated: cartilage-specific Egfr knockout (CKO) mice at 2 months after surgical destabilization of the medial meniscus (DMM), aged Egfr CKO mice, wild-type (WT) mice at 10 months after DMM, and WT mice after DMM plus hemisectomy of the meniscus (DMMH) surgery. Additionally, SOST (Sclerostin) KO mice were subjected to DMMH surgery. Knee joints were examined by microCT, histology, and immunohistochemistry.

RESULTS:

3D microCT analysis of the mouse distal femur revealed a positive correlation between SBP thickness and the loading status in normal knees. In late OA models, 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 of Sclerostin in osteocytes within the SBP. Unlike WT, SOST KO mice did not further increase SBP thickness in response to DMMH.

CONCLUSIONS:

Since focal stress on SBP underlying the cartilage damage site increases at late OA, our work establishes mechanical loading-induced attenuation of Sclerostin and elevation of bone formation along the SBP surface as the major mechanism for subchondral bone phenotypes associated with late stage OA in mice.

Item Type: Article
Date Deposited: 11 Nov 2017 00:45
Last Modified: 11 Nov 2017 00:45
URI: https://oak.novartis.com/id/eprint/33699

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