Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β-Catenin Signaling

Oxford University Press (OUP) - Tập 24 Số 10 - Trang 1651-1661 - 2009
Chuwen Lin1,2,3,4, Xuan Jiang3,4, Zhongquan Dai5,4, Xizhi Guo1, Tujun Weng6, Jun Wang7, Yinghui Li5, Guoyin Feng1, Xiang Gao1,3, Lin He1,2,8
1Bio-X Center, Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
2Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai, China
3Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, Nanjing University, Nanjing, China
4these authors contributed equally to this work
5Laboratory of Space Cell and Molecular Biology, China Astronaut Research and Training Center, Beijing, China
6Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
7Orthopaedic Institute of PLA, Xijing Hospital, the Fourth Military Medical University, Xi'an, China
8Institutes of Biomedical Sciences, Fudan University, Shanghai, China

Tóm tắt

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/β-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/β-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/β-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/β-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis.

Từ khóa


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Oxford University Press (OUP)

Tập 24 Số 10

1651-1661

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