Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways.
Sclerostin is expressed by osteocytes and has catabolic effects on bone. It has been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity, although at present the underlying mechanisms are unclear. Consistent with previous findings, Sclerostin opposed direct Wnt3a-induced but not direct BMP7-induced responses when both ligand and antagonist were provided exogenously to cells. However, we found that when both proteins are expressed in the same cell, sclerostin can antagonize BMP signaling directly by inhibiting BMP7 secretion. Sclerostin interacts with both the BMP7 mature domain and pro-domain, leading to intracellular retention and proteasomal degradation of BMP7. Analysis of sclerostin knock-out mice revealed an inhibitory action of sclerostin on Wnt signaling in both osteoblasts and osteocytes in cortical and cancellous bones. BMP7 signaling was predominantly inhibited by sclerostin in osteocytes of the calcaneus and the cortical bone of the tibia. Our results suggest that sclerostin exerts its potent bone catabolic effects by antagonizing Wnt signaling in a paracrine and autocrine manner and antagonizing BMP signaling selectively in the osteocytes that synthesize simultaneously both sclerostin and BMP7 proteins.
Department of Molecular Cell Biology and Centre for Biomedical Genetics, Julius-von-Sachs Institut für Biowissenschaften der UniversitätWürzburg, D-97074 Würzburg, Germany.
Carola
C
Krause
Olexandr
O
Korchynskyi
Karien
K
de Rooij
Stella E
SE
Weidauer
David J J
DJ
de Gorter
Rutger L
RL
van Bezooijen
Sarah
S
Hatsell
Aris N
AN
Economides
Thomas D
TD
Mueller
Clemens W G M
CW
Löwik
Peter
P
ten Dijke
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000737:chemistry*; D019485:Bone Morphogenetic Proteins / Q000737:chemistry* / Q000502:physiology; D005260:Female; D005819:Genetic Markers / Q000502:physiology*; D006023:Glycoproteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C422903:SOST protein, human; C486030:Sost protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; C525820:bmp7 protein, mouse