Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 14 S15.1

ECE2007 Symposia Novel bone hormones and regulators (4 abstracts)

Sclerostin, an osteocyte-produced regulator of bone formation

Socrates Papapoulos


Leiden University Medical Center, Leiden, Netherlands.


Sclerosteosis and van Buchem disease are closely related, rare sclerosing disorders characterized by substantial increase in bone mass of good quality which is due to increased bone formation. Both diseases have been linked to deficiency of the SOST gene product sclerostin, which in the adult is localized exclusively in osteocytes, the most abundant bone cell. In particular sclerostin is localized in mature osteocytes in mineralised cortical and cancellous bone, it inhibits the activity of osteoblasts and prevents them from promoting excessive bone formation. It is, thus, a negative regulator of bone formation. Sclerostin may be transported by the canaliculi to the bone surface where it inhibits the bone-forming activity of osteoblasts\. In this respect it serves the function of the unknown inhibitory factor proposed by Marotti and Martin that is secreted by mature osteocytes and communicates with osteoblasts at a forming surface causing the adjacent osteoblast to slow osteoid formation.

Because of its structural similarity to the DAN family of glycoproteins, it was originally thought that sclerostin is a BMP antagonist. Whilst sclerostin inhibits BMP-stimulated bone formation, it does not affect BMP signaling and is distinct from classical BMP antagonists. Instead it antagonizes Wnt signaling in osteoblastic cells.

The human high bone mass (HBM) phenotype is an autosomal dominant condition that, like sclerosteosis and van Buchem disease, is characterized by increased bone mass due to enhanced bone formation in the presence of normal bone resorption. It is due to mutations of the LRP5 gene that make it resistant to the inhibitory action of Dkk1, thereby increasing Wnt signalling. The observations that sclerostin antagonizes Wnt signaling rather than BMP signaling raises the possibility that these skeletal diseases are due to increased activity of the same signaling pathway: LRP5-mediated canonical Wnt signaling.

The restricted expression pattern of sclerostin and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem diseases provide a basis for the design of therapeutics that specifically stimulate bone formation, an action of primary importance for the management of patients with osteoporosis. As sclerostin is a secreted protein, one approach to achieve this is to develop humanized monoclonal antibodies capable of inhibiting the biological activity of sclerostin, mimicking, thus, the absence of sclerostin in sclerosteosis. Preliminary results of such approaches in animal models have been very encouraging.

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