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 journalArticle

248 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)209-217
Number of pages9
JournalBone
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2012

Fingerprint

Osteogenesis
Transgenic Mice
Down-Regulation
Osteocytes
Ulna
Transgenes
Minerals
Weight-Bearing
Osteoblasts
Gene Expression
Bone and Bones
Messenger RNA
Genes

Keywords

  • Bone formation
  • Mechanical loading
  • Osteocytes
  • Sclerostin
  • Sost
  • Wnt signaling

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. / Tu, Xiaolin; Rhee, Yumie; Condon, Keith W.; Bivi, Nicoletta; Allen, Matthew R.; Dwyer, Denise; Stolina, Marina; Turner, Charles H.; Robling, Alexander G.; Plotkin, Lilian I.; Bellido, Teresita.

In: Bone, Vol. 50, No. 1, 01.01.2012, p. 209-217.

Research output: Contribution to journalArticle

Tu, Xiaolin ; Rhee, Yumie ; Condon, Keith W. ; Bivi, Nicoletta ; Allen, Matthew R. ; Dwyer, Denise ; Stolina, Marina ; Turner, Charles H. ; Robling, Alexander G. ; Plotkin, Lilian I. ; Bellido, Teresita. / Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. In: Bone. 2012 ; Vol. 50, No. 1. pp. 209-217.
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AU - Dwyer, Denise

AU - Stolina, Marina

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