Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading

Xiaolin Tu, Yumie Rhee, Keith W. Condon, Nicoletta Bivi, Matthew R. Allen, Denise Dwyer, Marina Stolina, Charles H. Turner, Alexander G. Robling, Lilian I. Plotkin, Teresita Bellido

Research output: Contribution to journalArticlepeer-review

362 Citations (Scopus)


Sclerostin, the Wnt signaling antagonist encoded by the Sost gene, is secreted by osteocytes and inhibits bone formation by osteoblasts. Mechanical stimulation reduces sclerostin expression, suggesting that osteocytes might coordinate the osteogenic response to mechanical force by locally unleashing Wnt signaling. To investigate whether sclerostin downregulation is a pre-requisite for load-induced bone formation, we conducted experiments in transgenic mice (TG) engineered to maintain high levels of SOST expression during mechanical loading. This was accomplished by introducing a human SOST transgene driven by the 8. kb fragment of the DMP1 promoter that also provided osteocyte specificity of the transgene. Right ulnae were subjected to in vivo cyclic axial loading at equivalent strains for 1. min/day at 2. Hz; left ulnae served as internal controls. Endogenous murine Sost mRNA expression measured 24. h after 1 loading bout was decreased by about 50% in TG and wild type (WT) littermates. In contrast, human SOST, only expressed in TG mice, remained high after loading. Mice were loaded on 3 consecutive days and bone formation was quantified 16. days after initiation of loading. Periosteal bone formation in control ulnae was similar in WT and TG mice. Loading induced the expected strain-dependent increase in bone formation in WT mice, resulting from increases in both mineralizing surface (MS/BS) and mineral apposition rate (MAR). In contrast, load-induced bone formation was reduced by 70-85% in TG mice, due to lower MS/BS and complete inhibition of MAR. Moreover, Wnt target gene expression induced by loading in WT mice was absent in TG mice. Thus, downregulation of Sost/sclerostin in osteocytes is an obligatory step in the mechanotransduction cascade that activates Wnt signaling and directs osteogenesis to where bone is structurally needed.

Original languageEnglish
Pages (from-to)209-217
Number of pages9
Issue number1
Publication statusPublished - 2012 Jan

Bibliographical note

Funding Information:
The authors thank R. Lee and J.D. Benson for technical assistance. This research was supported by the National Institutes of Health ( R01DK076007 and an American Recovery and Reinvestment Act supplement).

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology


Dive into the research topics of 'Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading'. Together they form a unique fingerprint.

Cite this