Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling.
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.
Bio-X Center, Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
Chuwen
C
Lin
Xuan
X
Jiang
Zhongquan
Z
Dai
Xizhi
X
Guo
Tujun
T
Weng
Jun
J
Wang
Yinghui
Y
Li
Guoyin
G
Feng
Xiang
X
Gao
Lin
L
He
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000378:metabolism*; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control; D001842:Bone and Bones / Q000473:pathology / Q000502:physiology*; D017353:Gene Deletion; D018390:Gene Targeting; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D009929:Organ Size; D010006:Osteoblasts / Q000473:pathology; D010011:Osteocytes / Q000473:pathology; D010012:Osteogenesis; D015398:Signal Transduction; D013314:Stress, Mechanical; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin