Sclerosteosis and Van Buchem disease are rare, high-bone-mass disorders that have been linked to deficiency in the SOST gene, encoding sclerostin. Sclerostin belongs to the DAN family of glycoproteins, of which multiple family members have been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity. Sclerostin is specifically expressed by osteocytes and inhibits BMP-induced osteoblast differentiation and ectopic bone formation. Sclerostin binds only weakly to BMPs and does not inhibit direct BMP-induced responses. Instead, sclerostin antagonizes canonical Wnt signaling by binding to Wnt coreceptors, low-density lipoprotein receptor-related protein 5 and 6. Several lipoprotein receptor-related protein-5 mutants that cause the high-bone-mass trait are defective in sclerostin binding. Thus, high bone mass in sclerosteosis and Van Buchem disease may result from increased Wnt signaling due to the absence of or insensitivity to sclerostin.

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.Sclerosteosis (OMIM accession number 269500) and van Buchem disease (OMIM accession number 239100) are closely related, rare high bone mass disorders that have been linked to a deficiency in expression of sclerostin, encoded by the SOST gene (1-8). Sclerostin is an osteocyte-derived negative regulator of bone formation belonging to the DAN family of secreted glycoproteins. Members of the DAN family were shown to have the capacity to inhibit BMP and/or Wnt activity (9 -13). Because sclerostin binds, albeit weakly, to mature bone morphogenetic proteins (BMPs), 4 it initially was presumed to be a BMP antagonist; however, currently sclerostin is believed to mediate its inhibitory effect on bone formation by directly blocking the Wnt signaling pathway (9, 14, 15).Canonical Wnt signaling has been described to play a crucial role in several bone mass disorders. Wnt proteins transduce their signals via seven-transmembrane-spanning receptors of the frizzled family and lipoprotein receptor-related protein-5/6 (LRP5/6), thereby controlling the stability of cytoplasmic ␤-catenin. In the absence of Wnt ligands, ␤-catenin forms a complex with APC (adenomatous polyposis coli), axin, GSK3 (glycogen synthase kinase 3), and CK1 (casein kinase I). This complex facilitates phosphorylation and subsequent proteasomal degradation of ␤-catenin. In the presence of Wnt ligands, this complex dissociates, and ␤-catenin accumulates and translocates into the nucleus, where it forms complexes with TCF/Lef1 transcription factors and initiates transcription of target genes (16). The importance of Wnt signaling in bone formation is illustrated by the low bone mass osteoporosis-pseudoglioma syndrome or high bone mass phenotype caused by missense loss or gain of function mutations in LRP5,. Sclerostin was found to ac...

Bone morphogenetic proteins (BMPs) are used clinically to induce new bone formation in spinal fusions and long bone nonunion fractures. However, large amounts of BMPs are needed to achieve these effects. BMPs were found to increase the expression of antagonists, which potentially limit their therapeutic efficacy. However, the relative susceptibility of osteoinductive BMPs to different antagonists is not well characterized. Here we show that BMP-6 is more resistant to noggin inhibition and more potent in promoting osteoblast differentiation in vitro and inducing bone regeneration in vivo when compared with its closely related BMP-7 paralog. Noggin was found to play a critical role as a negative feedback regulator of BMP-7 but not BMP-6-induced biological responses. Using BMP-6/7 chimeras, we identified lysine 60 as a key residue conferring noggin resistance within the BMP-6 protein. A remarkable correlation was found between the presence of a lysine at this position and noggin resistance among a panel of osteoinductive BMPs. Introduction of a lysine residue at the corresponding positions of BMP-2 and BMP-7 allowed for molecular engineering of recombinant BMPs with increased resistance to noggin antagonism. Bone morphogenetic proteins (BMPs)3 are dimeric secreted cytokines that were discovered based on their ability to induce ectopic bone and cartilage formation in vivo (1-4). BMPs belong to the transforming growth factor-␤ superfamily, which also includes transforming growth factors-␤ and activins. Over 15 distinct BMP family members have been identified that signal via specific BMP type I and type II serine/threonine kinase receptors (5). Three BMP type II receptors (BMPR-II (BMP type II receptor), ActR-II (activin type II receptor), and ActR-IIB) and four distinct BMP type I receptors (ALK1 (activin receptor-like kinase 1), ALK2, ALK3, and ALK6) have been described (5-8). Cell surface binding of BMPs to their receptors results in heteromeric complex formation, upon which the constitutively active type II receptor phosphorylates the type I receptor on specific serine and threonine residues in the juxtamembrane region. Different BMPs bind with different affinities and specificities to different BMPR complexes (6 -10). The activated BMP type I receptor initiates intracellular signaling by phosphorylating specific receptor-regulated Smad (R-Smad) proteins (Smad1, Smad5, and Smad8). Activated R-Smads form heteromeric complexes with Smad4, which translocate to the nucleus and regulate, in cooperation with transcriptional coactivators and co-repressors, the transcription of target genes (5). BMP signaling is controlled at different levels by both positive and negative regulators. At the extracellular level, BMP antagonists bind BMPs and interfere with their binding to BMP receptors. An important extracellular BMP antagonist of the osteogenic activity of BMPs is noggin. The crystal structure of the noggin-BMP-7 complex demonstrated that binding of noggin to BMPs resembles that of BMP receptors and thereby prevents the ...

No abstract

Metabologens initiate, promote and maintain morphogenesis and adult tissue homeostasis. Bone morphogenetic proteins (BMPs) which belong to the transforming growth factor-β (TGF-β) superfamily, represent a major class of metabologens that regulate ectoderm, mesoderm and endoderm derived tissue formation. In order to temporally and spatially control BMP initiated signaling cascades, a tight regulatory network is needed to maintain concinnity. There are a number of ways how BMP signaling can be inhibited or more likely be modified, among which the direct extracellular inhibition through cysteine-knot containing proteins from the DAN-, the twisted gastrulation-, chordin- and noggin-family is a classic. This review focuses on noggin and its impact on the vast array of BMP driven actions and thereby invites the ever-growing BMP research field to (re-) investigate noggin's function in detail.