Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)

Abstract

Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.

Building bone with a SOST-PTH partnership

“…In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis, (12) trabecular bone volume was more than double that of wild-type mice. For this reason, the effects of PTH were studied in young (6-to 8-week old) mice.…”

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

“…(7)(8)(9) This was further highlighted by the high-bone-mass phenotype of SOST knockout mice and the substantial increases in bone formation and bone strength found in both the trabecular and cortical bone compartments of these animals.…”

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

“…(11)(12)(13)(14) Humans with inherited sclerostin deficiency (sclerosteosis or van Buchem disease) have increased bone mass and are resistant to fracture. (15,16) Sclerostin knockout mice have greater bone mass and bone strength owing to increased bone formation.…”