Modulation of sclerostin expression by mechanical loading and bone morphogenetic proteins in osteogenic cells.
The anabolic effect of dynamic mechanical loading on skeletal architecture has been repeatedly demonstrated, but the cellular and molecular events occurring between load and ultimate bone formation remain obscure. The discovery of sclerostin, an antagonist of Wnt/Lrp5 signaling, and the sclerosing bone dysplasias that result from its mutation suggest its pivotal role in modulating bone formation. We examined expression of Sost mRNA across a variety of clonal cell lines spanning the osteogenic phenotype from immature osteoblast to mature osteocyte. No sclerostin expression was detected in immature MC3T3-E1 osteoblasts and, surprisingly, mature MLO-Y4 osteocytes, whereas immature MLO-A5 osteocytic cells expressed very low levels of Sost. Highest expression was observed in mature UMR 106.01 osteoblasts. We examined the influence of bone morphogenetic proteins on Sost expression. Treatment with BMP-2, -4 or -6 was without effect on Sost in mature MLO-Y4 osteocytes but elicited a robust increase in Sost expression in immature MLO-A5 osteocytes. Oscillatory fluid flow applied to mature UMR 106.01 osteoblasts transiently decreased expression of sclerostin at both the mRNA and protein level. Overall, our results indicate that BMP treatment and in vitro mechanical loading demonstrate opposite effects upon sclerostin expression.
Papanicolaou
Savvas E
SE
Lawrence J. Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of California at Davis, Sacramento, CA, USA.
Phipps
Roger J
RJ
Fyhrie
David P
DP
Genetos
Damian C
DC
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D005819:Genetic Markers / Q000235:genetics; D006023:Glycoproteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D010011:Osteocytes / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; C486030:Sost protein, mouse; D051153:Wnt Proteins