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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Animals, Newborn
  • Apoptosis
  • Bone Morphogenetic Proteins / deficiency
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control
  • Bone and Bones / pathology
  • Bone and Bones / physiology*
  • Gene Deletion
  • Gene Targeting
  • Genetic Markers
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Models, Biological
  • Organ Size
  • Osteoblasts / pathology
  • Osteocytes / pathology
  • Osteogenesis
  • Signal Transduction*
  • Stress, Mechanical*
  • Up-Regulation
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Sost protein, mouse
  • Wnt Proteins
  • beta Catenin