Sclerostin Is a Novel Secreted Osteoclast-derived Bone Morphogenetic Protein Antagonist with Unique Ligand Specificity

Abstract

Sclerosteosis is a progressive sclerosing bone dysplasia. Sclerostin (the SOST gene) was originally identified as the sclerosteosis-causing gene. However, the physiological role of sclerostin remains to be elucidated. Sclerostin was intensely expressed in developing bones of mouse embryos. Punctuated expression of sclerostin was localized on the surfaces of both intramembranously forming skull bones and endochondrally forming long bones. Sclerostin-positive cells were identified as osteoclasts. Recombinant sclerostin protein produced in cultured cells was efficiently secreted as a monomer. We examined effects of sclerostin on the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells. Sclerostin inhibited the BMP6 and BMP7 activity but not the BMP2 and BMP4 activity. Sclerostin bound to BMP6 and BMP7 with high affinity but bound to BMP2 and BMP4 with lower affinity. In conclusion, sclerostin is a novel secreted osteoclast-derived BMP antagonist with unique ligand specificity. We suggest that sclerostin negatively regulates the formation of bone by repressing the differentiation and/or function of osteoblasts induced by BMPs. Since sclerostin expression is confined to the bone-resorbing osteoclast, it provides a mechanism whereby bone apposition is inhibited in the vicinity of resorption. Our findings indicate that sclerostin plays an important role in bone remodeling and links bone resorption and bone apposition.Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Scleroteosis is clinically and radiologically very similar to van Buchem disease (1, 2). By linkage analysis of families with these diseases, the disease-causing genes were mapped to the same chromosomal 17q12-q21 region, supporting the hypothesis that both diseases are caused by mutations in the same gene. By the positional cloning strategy, sclerostin (the SOST gene), which was mutated in sclerosteosis patients, was identified (1, 2). Sclerostin was found to be expressed in human long bones and cartilage using the polymerase chain reaction. However, the expression of sclerostin in the bones and cartilage was not examined in detail. The pathogenesis and genetics of sclerosteosis suggest that inhibition of sclerostin could lead to increased bone density. This definitely makes sclerostin and its pathway interesting targets for the development of anabolic agents against osteoporosis (1, 2). Sclerostin encodes a protein of 213 amino acids with a putative signal peptide for secretion, and sclerostin has six conserved cysteine residues and one conserved glycine residue that are essential to form a cystine knot. The spacing of cysteine residues is highly homologous to that of bone morphogenetic protein (BMP) 1 antagonists of the DAN/ cerberus family, indicating that sclerostin might be a BMP antagonist (1, 2). However, the biological activity of sclerostin is not known. Therefore, the physiological role of sclerostin and its mechanism of action remain to be elucidated.We examined t...

Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis

“…We therefore exposed HCMLs to BMP6 inhibitors noggin (Kersten et al, 2006) and sclerostin (Kusu et al, 2003). Both sclerostin and noggin exposure yielded a concentration-dependent increase of proliferation.…”

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

“…The following biochemical parameters were measured because of their novelty or correlation with bone parameters in cross-sectional prior studies: serum parathyroid hormone (PTH; commonly used to assess bone turnover abnormalities, which have been shown to be associated with changes in bone volume) (12), bone-specific alkaline phosphatase (BSAP) and procollagen type 1 N-terminal propeptide (P1NP; which are markers of osteoblastic activity) (13,14), tartrate-resistant acid phosphatase-5b (TRAP-5b; a marker of osteoclastic activity) (15), sclerostin (a protein produced by osteocytes [16,17] and expressed at bone formation sites [18,19]), Dickkopf-1 (DKK-1; found in bone and other tissues [20], and like sclerostin, it leads to increased bone formation and bone volume when knocked out) (21,22), and fibroblast growth factor 23 (FGF23; involved in mineral metabolism with a role in bone mineralization/remodeling) (23)(24)(25). In addition, serum calcium and phosphorus were measured.…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…In addition to these Wnt pathway findings, sclerostin had been reported to regulate the bone morphogenetic protein (BMP) pathway by binding to and antagonizing the activity of BMPs, (39,40) as well as Noggin, (41) itself a well-known BMP antagonist.…”