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...

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In this report, we deal with the isolation of a novel vasorelaxing peptide from a chymotryptic digest of ovalbumin and its vasorelaxing activities. This peptide is composed of ArgAla-Asp-His-Pro-Phe (RADHPF) in its sequence, corresponding to residues 359^364 of ovalbumin. This peptide (30^300 W WM) exerted a dose-dependent vasodilation in an isolated mesenteric artery from a spontaneously hypertensive rat which was preconstricted by phenylephrine, besides the relaxation being endothelium-dependent. It is noteworthy that the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester inhibited this relaxation, implying involvement of nitric oxide in its mechanism of action. Following oral administration of RADHPF at a dose of 10 mg/kg, the systolic blood pressure in a spontaneously hypertensive rat was significantly lowered.z 1999 Federation of European Biochemical Societies.

Four new inhibitory peptides for angiotensin I-converting enzyme (ACE), that is, MRWRD, MRW, LRIPVA, and IAYKPAG, were isolated from the pepsin-pancreatin digest of spinach Rubisco with the use of HPLC. IC(50) values of individual peptides were 2.1, 0.6, 0.38, and 4.2 microM, respectively. MRW and MRWRD had an antihypertensive effect after oral administration to spontaneously hypertensive rats. Maximal reduction occurred 2 h after oral administration of MRW, whereas MRWRD showed maximal decrease 4 h after oral administration at doses of 20 and 30 mg/kg, respectively. IAYKPAG also exerted antihypertensive activity after oral administration at the dose of 100 mg/kg, giving a maximum decrease 4 h after oral administration. IAYKP, IAY, and KP, the fragment peptides of IAYKPAG, also exerted antihypertensive activity. LRIPVA [corrected] did not show any antihypertensive effect at a dose of 100 mg/kg despite its potent ACE-inhibitory activity.