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J Bone Miner Res. 2009 Oct;24(10):1651-61. doi: 10.1359/jbmr.090411.

Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling.

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1
Bio-X Center, Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/beta-catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/beta-catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost(-/-) mice were resistant to mechanical unloading-induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/beta-catenin signaling was not altered by unloading in Sost(-/-) mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/beta-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis.

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PMID:
19419300
DOI:
10.1359/jbmr.090411
[Indexed for MEDLINE]
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