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CYR61/CCN1 Regulates Sclerostin Levels and Bone Maintenance

  1. Author:
    Zhao, Gexin
    Huang, Bau-Lin
    Rigueur, Diana
    Wang, Weiguang
    Bhoot, Chimay
    Charles, Kemberly R
    Baek, Jongseung
    Mohan, Subburaman
    Jiang, Jie
    Lyons, Karen M

  2. Author Address

    Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA., Center for Cancer Research, National Cancer Institute, Frederick, MD, USA., Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles Los Angeles, CA, USA., Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA, USA., Department of Medicine, Loma Linda University, Loma Linda, CA, USA., School of Dentistry, University of California, Los Angeles Los Angeles, CA, USA., Hemophilia Treatment Center, Orthopaedic Institute for Children, Los Angeles, CA, USA.,
    1. Year: 2018
    2. Date: Jun
    3. Epub Date: 2018 01 19
  2. Journal: Journal of Bone and Mineral Research
    1. 33
    2. 6
    3. Pages: 1076-1089
  4. Type of Article: Article
  1. Abstract:

    CYR61/CCN1 is a matricellular protein that resides in the extracellular matrix, but serves regulatory rather than structural roles. CYR61/CCN1 is found in mineralized tissues and has been shown to influence bone healing in vivo and osteogenic differentiation in vitro. In this study we generated Cyr61 bone specific knockout mice to examine the physiological role of CYR61/CCN1 in bone development and maintenance in vivo. Extensive analysis of Cyr61 conditional knockout mice showed a significant decrease in both trabecular and cortical bone mass as compared to WT littermate. Our data suggest that CYR61/CCN1 exerts its effects on mature osteoblast/osteocyte function to modulate bone mass. Specifically, changes were observed in osteocyte/osteoblast expression of RankL VegfA and Sost. The increase in RankL expression was correlated with a significant increase in osteoclast number; decreased VegfA expression was correlated with a significant decrease bone vasculature; increased Sost expression was associated with decreased Wnt signaling, as revealed by decreased Axin2 expression and increased adiposity in the bone marrow. While the decreased number of vascular elements in bone likely contributes to the low bone mass phenotype in Cyr61 conditional knockout mice, this cannot explain the observed increase in osteoclasts and the decrease in Wnt signaling. We conducted in vitro assays using UMR-106 osteosarcoma cells to explore the role CYR61/CCN1 plays in modulating Sost mRNA and protein expression in osteocytes and osteoblasts. Overexpression of CYR61/CCN1 can suppress Sost expression in both control and Cyr61 knockout cells, and blocking Sost with siRNA can rescue Wnt responsiveness in Cyr61 knockout cells in vitro. Overall, our data suggests that CYR61/CCN1 modulates mature osteoblast and osteocyte function to regulate bone mass through both angiogenic effects as well as by modulating Wnt signaling, at least in part through the Wnt antagonist Sost. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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External Sources

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  2. DOI: 10.1002/jbmr.3394
  3. PMID: 29351359
  4. PMCID: PMC6002906
  5. View record in Web of Science®
  6. WOS: 000435276500013

Library Notes

  1. Fiscal Year: FY2017-2018
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