Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts.
SOST, a novel bone morphogenetic protein (BMP) antagonist and negative regulator of bone formation, is expressed in osteogenic cells. Null mutations in the SOST gene are associated with the sclerosteosis phenotype typified by high bone mass. We sought to delineate the pathways involved in the regulation of SOST expression in human osteoblastic cells. We evaluated the effects of bone growth factors and hormones on the RNA levels of SOST and the BMP antagonists, noggin and gremlin. Parathyroid hormone (PTH), transforming growth factor-beta1 (TGF-beta1), fibroblast growth factors 1 and 2 (FGF1, FGF2), and insulin-like growth factor-1 (IGF-1) had negligible effects on SOST expression in human osteoblasts. In comparison, BMPs-2, 4, and 6 induced the message levels of SOST in a time- and dose-dependent manner. The levels of noggin and, to a lesser extent, gremlin were also increased by BMPs. BMP's stimulatory effects on SOST were further enhanced by retinoic acid or 1,25-dihydroxyvitamin D3. In contrast, dexamethasone (DEX) blocked the effects of the BMPs on SOST and gremlin, but not on noggin. Retinoic acid and 1,25-dihydroxyvitamin D3 did not affect the BMP-enhanced expression of gremlin or noggin. The steroids did not affect the endogenous levels of the BMP antagonists. These findings show that the levels of SOST are modulated by BMPs and the interactions of the BMPs with steroid hormones in human osteoblasts. These effects differed markedly from that of noggin or gremlin, suggesting that there is an exquisite regulation of the expressions of BMP antagonists in cells of the osteoblast lineage.
Department of Gene Function and Target Validation, Celltech R&D, Inc., Bothell, WA 98021, USA.
May Kung
MK
Sutherland
James C
JC
Geoghegan
Changpu
C
Yu
David G
DG
Winkler
John A
JA
Latham
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000502:physiology*; D002117:Calcitriol / Q000494:pharmacology*; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D010006:Osteoblasts / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D005819:Genetic Markers; C422903:SOST protein, human; D003907:Dexamethasone; D002117:Calcitriol