Title
Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation
Author
van Bezooijen, R.L.
Svensson, J.P.
Eefting, D.
Visser, A.
van der Horst, G.
Karperien, M.
Quax, P.H.A.
Vrieling, H.
Papapoulos, S.E.
ten Dijke, P.
Löwik, W.G.M.C.
TNO Kwaliteit van Leven
Publication year
2007
Abstract
Sclerostin is an osteocyte-derived negative regulator of bone formation. It inhibits BMP-stimulated bone formation both in vitro and in vivo but has no direct effect on BMP signaling. Instead, sclerostin inhibits Wnt signaling that is required for BMP-stimulated osteoblastic differentiation. Introduction: Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize BMP activity. Sclerostin has been shown to inhibit BMP-stimulated bone formation, but its mechanism of action seems to be different from classical BMP antagonists. In this study, we investigated the mechanism by which sclerostin inhibits BMP-stimulated bone formation. Materials and Methods: DNA electroporation of calf muscle of mice using expression plasmids for BMP and sclerostin was used to study the effect of sclerostin on BMP-induced bone formation in vivo. Transcriptional profiling using microarrays of osteoblastic cells treated with BMP in the absence or presence of sclerostin was used to find specific growth factor signaling pathways affected by sclerostin. The affected pathways were further studied using growth factor-specific reporter constructs. Results: BMP-induced ectopic bone formation in calf muscle of mice was prevented by co-expression of sclerostin in vivo. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways. Sclerostin, however, did not inhibit stimulation of direct BMP target genes. Furthermore, we did not obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP-specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMP- and Wnt-induced Wnt reporter construct activation. Conclusions: Sclerostin inhibits BMP-stimulated bone formation but does not affect BMP signaling. Instead, it antagonizes Wnt signaling in osteoblastic cells. High bone mass in sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling. © 2007 American Society for Bone and Mineral Research.
Subject
Biology
Biomedical Research
BMP
Bone formation
Microarray
Sclerostin
Signal transduction
SOST
Wnt
Bone morphogenetic protein
Dickkopf 1 protein
Glycoprotein
Growth factor
Protein inhibitor
Sclerostin
Wnt protein
Animal cell
Animal experiment
Animal tissue
Bone disease
Bone mass
Cell differentiation
Controlled study
DNA microarray
Electroporation
Embryo
Expression vector
Gastrocnemius muscle
Gene
Gene expression profiling
Gene targeting
Genetic transcription
Human
Human cell
In vivo study
Male
Mouse
Nonhuman
Ossification
Osteoblast
Osteocyte
Osteosclerosis
Protein family
Reporter gene
Signal transduction
SOST gene
Van buchem disease
Animals
Bone Development
Bone Morphogenetic Proteins
Cells, Cultured
Electroporation
Gene Expression Regulation
Genes, Reporter
Genetic Markers
Humans
Mesoderm
Mice
Muscle, Skeletal
Oligonucleotide Array Sequence Analysis
Recombinant Proteins
Signal Transduction
Transfection
Wnt Proteins
To reference this document use:
http://resolver.tudelft.nl/uuid:6367c486-cfd3-48b9-87ec-0949445048db
DOI
https://doi.org/10.1359/jbmr.061002
TNO identifier
239789
ISSN
0884-0431
Source
Journal of Bone and Mineral Research, 22 (1), 19-28
Document type
article