Sclerostin, the product of the SOST

SOST

Sclerostin is a protein that in humans is encoded by the SOST gene.-External links:*-Further reading:...

 gene, located on chromosome 17, locus q11.2 in humans, was originally believed to be a non-classical Bone morphogenetic protein

Bone morphogenetic protein

Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...

 (BMP) antagonist. More recently Sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signalling pathway . Wnt pathway inhibition under these circumstances is antagonistic to bone formation (meaning Sclerostin antagonizes bone formation). Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signalling, but not BMP signalling pathways.

Mutations of Sclerostin is associated with the syndrome Sclerosteosis in which there is an abnormal increase in the growth of bones due to lack of normal Sclerostin expression by osteocytes and a different set of mutations in the non-coding region of sclerostin are associated with Van Buchem's syndrome, a similar high bone mass phenotype. Sclerostin acts upon osteoblasts in the bone in a paracrine manner of unknown mechanism.

Currently an anti-Sclerostin antibody

Antibody

An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 for the treatment of osteoporosis

Osteoporosis

Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 is being co-developed by Amgen

Amgen

Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...

 and UCB

UCB (company)

UCB is a multinational biopharmaceutical manufacturing company headquartered in Brussels, Belgium.- History :UCB was founded on 18 January 1928 by Emmanuel Janssen, a Belgian businessman...

.

OsteoGeneX Inc is developing and commercializing first in class sclerostin small molecule inhibitors (www.osteogenex.com).

Sclerostin is produced by the osteocyte

Osteocyte

An osteocyte, a star-shaped cell, is the most abundant cell found in compact bone. Cells contain a nucleus and a thin ring of cytoplasm. When osteoblasts become trapped in the matrix they secrete, they become osteocytes...

 and has catabolic effects on bone formation. This protein, with a length of 213 residues, has a dssp secondary structure that is 28% beta sheet (6 strands; 32 residues). Sclerostin has an inhibitory effect on the lifetime of the osteoblast. Sclerostin production by osteocytes is inhibited by parathyroid hormone

Parathyroid hormone

Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...

, mechanical loading and cytokines including oncostatin M

Oncostatin M

Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory factor in both structure and function...

, cardiotrophin-1 and leukemia inhibitory factor

Leukemia inhibitory factor

Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...

. Sclerostin production is increased by calcitonin

Calcitonin

Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...

. Thus, osteoblast activity is self regulated by a negative feedback system.