title: Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading.
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.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. xtu@iupui.edu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tu
authors.forename: Yumie
authors.initials: Y
authors.lastname: Rhee
authors.forename: Keith W
authors.initials: KW
authors.lastname: Condon
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bivi
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Charles H
authors.initials: CH
authors.lastname: Turner
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010011:Osteocytes / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical; D019076:Transgenes; D016474:Weight-Bearing / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C422903:SOST protein, human; C486030:Sost protein, mouse; D051153:Wnt Proteins
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