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    Distinct modes of inhibition by Sclerostin on bone morphogenetic protein and Wnt signaling pathways.

    J Biol Chem. 2010 Oct 15. [Epub ahead of print]

    These authors find that in addition to its well-known ability to inhibit Wnt signaling pathways, sclerostin can also antagonize bone morphogenetic protein (BMP) signaling directly by inhibiting BMP7 secretion. They demonstrate that sclerostin interacts with both the BMP7 mature- and pro-domain, leading to intracellular retention and proteasomal degradation of BMP7. The authors find that this effect occurred predominantly in osteocytes that secrete both sclerostin and BMP7.
    Authors: Krause C, Korchynskyi O, de Rooij KE, et. al

    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- 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- 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 BMP signaling selectively in the osteocytes that synthesize simultaneously both Sclerostin and BMP7 proteins.

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