Abstract
Mutations in sclerostin function or expression cause sclerosing bone dysplasias, involving decreased antagonism of Wnt/Lrp5 signaling. Conversely, deletion of the VHL tumor suppressor in osteoblasts, which stabilize HIF-α isoforms and thereby enables HIF-α/β-driven gene transcription, increases bone mineral content and cross-sectional area compared to wild-type controls. We examined the influence of cellular hypoxia (1% oxygen) upon sclerostin expression and canonical Wnt signaling. Osteoblasts and osteocytes cultured under hypoxia revealed decreased sclerostin transcript and protein, and increased expression and nuclear localization of activated β-catenin. Similarly, both hypoxia and the hypoxia mimetic DFO increased β-catenin gene reporter activity. Hypoxia and its mimetics increased expression of the BMP antagonists gremlin and noggin and decreased Smad-1/5/8 phosphorylation. As a partial explanation for the mechanism of regulation of sclerostin by oxygen, MEF2 reporter assays revealed decreased activity. Modulation of VEGF signaling under normoxia or hypoxia revealed no influence upon Sost transcription. These data suggest that hypoxia inhibits sclerostin expression, through enhanced antagonism of BMP signaling independent of VEGF.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 457-467 |
| Number of pages | 11 |
| Journal | Journal of Cellular Biochemistry |
| Volume | 110 |
| Issue number | 2 |
| DOIs | |
| State | Published - May 15 2010 |
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Keywords
- Bone morphogenetic protein
- Hypoxia
- Osteoblast
- Sclerostin
- Sost
- Wnt
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. / Genetos, Damian C; Toupadakis, Chrisoula A.; Raheja, Leah F.; Wong, Alice; Papanicolaou, Savvas E.; Fyhrie, David P; Loots, Gabriela G.; Yellowley-genetos, Clare E.
In: Journal of Cellular Biochemistry, Vol. 110, No. 2, 15.05.2010, p. 457-467.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts
AU - Genetos, Damian C
AU - Toupadakis, Chrisoula A.
AU - Raheja, Leah F.
AU - Wong, Alice
AU - Papanicolaou, Savvas E.
AU - Fyhrie, David P
AU - Loots, Gabriela G.
AU - Yellowley-genetos, Clare E
PY - 2010/5/15
Y1 - 2010/5/15
N2 - Mutations in sclerostin function or expression cause sclerosing bone dysplasias, involving decreased antagonism of Wnt/Lrp5 signaling. Conversely, deletion of the VHL tumor suppressor in osteoblasts, which stabilize HIF-α isoforms and thereby enables HIF-α/β-driven gene transcription, increases bone mineral content and cross-sectional area compared to wild-type controls. We examined the influence of cellular hypoxia (1% oxygen) upon sclerostin expression and canonical Wnt signaling. Osteoblasts and osteocytes cultured under hypoxia revealed decreased sclerostin transcript and protein, and increased expression and nuclear localization of activated β-catenin. Similarly, both hypoxia and the hypoxia mimetic DFO increased β-catenin gene reporter activity. Hypoxia and its mimetics increased expression of the BMP antagonists gremlin and noggin and decreased Smad-1/5/8 phosphorylation. As a partial explanation for the mechanism of regulation of sclerostin by oxygen, MEF2 reporter assays revealed decreased activity. Modulation of VEGF signaling under normoxia or hypoxia revealed no influence upon Sost transcription. These data suggest that hypoxia inhibits sclerostin expression, through enhanced antagonism of BMP signaling independent of VEGF.
AB - Mutations in sclerostin function or expression cause sclerosing bone dysplasias, involving decreased antagonism of Wnt/Lrp5 signaling. Conversely, deletion of the VHL tumor suppressor in osteoblasts, which stabilize HIF-α isoforms and thereby enables HIF-α/β-driven gene transcription, increases bone mineral content and cross-sectional area compared to wild-type controls. We examined the influence of cellular hypoxia (1% oxygen) upon sclerostin expression and canonical Wnt signaling. Osteoblasts and osteocytes cultured under hypoxia revealed decreased sclerostin transcript and protein, and increased expression and nuclear localization of activated β-catenin. Similarly, both hypoxia and the hypoxia mimetic DFO increased β-catenin gene reporter activity. Hypoxia and its mimetics increased expression of the BMP antagonists gremlin and noggin and decreased Smad-1/5/8 phosphorylation. As a partial explanation for the mechanism of regulation of sclerostin by oxygen, MEF2 reporter assays revealed decreased activity. Modulation of VEGF signaling under normoxia or hypoxia revealed no influence upon Sost transcription. These data suggest that hypoxia inhibits sclerostin expression, through enhanced antagonism of BMP signaling independent of VEGF.
KW - Bone morphogenetic protein
KW - Hypoxia
KW - Osteoblast
KW - Sclerostin
KW - Sost
KW - Wnt
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UR - http://www.scopus.com/inward/citedby.url?scp=77952027256&partnerID=8YFLogxK
U2 - 10.1002/jcb.22559
DO - 10.1002/jcb.22559
M3 - Article
C2 - 20336693
AN - SCOPUS:77952027256
VL - 110
SP - 457
EP - 467
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
SN - 0730-2312
IS - 2
ER -