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    4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts.

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    Author
    Scheiber, Amanda L
    Wilkinson, Kevin J
    Suzuki, Akiko
    Enomoto-Iwamoto, Motomi
    Kaito, Takashi
    Cheah, Kathryn Se
    Iwamoto, Masahiro
    Leikin, Sergey
    Otsuru, Satoru
    Date
    2022-02-08
    Journal
    JCI Insight
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/jci.insight.149636
    Abstract
    Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts, and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.
    Keyword
    Bone Biology
    Cartilage
    Cell Biology
    Cell stress
    Genetic diseases
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17947
    ae974a485f413a2113503eed53cd6c53
    10.1172/jci.insight.149636
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