Sclerostin is a
protein that in humans is encoded by the SOSTgene.[5] It is a secreted
glycoprotein with a
C-terminalcysteine knot-like (CTCK) domain and sequence similarity to the
DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the
osteocyte but is also expressed in other tissues,[6] and has anti-anabolic effects on bone formation.[7]
Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[9] was originally believed to be a non-classical
bone morphogenetic protein (BMP) antagonist.[10] More recently, sclerostin has been identified as binding to
LRP5/
6 receptors and inhibiting the
Wnt signaling pathway.[11][12] The inhibition of the Wnt pathway leads to decreased bone formation.[11] Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signaling, but not BMP signaling pathways.[13][14] Sclerostin is expressed in
osteocytes and some
chondrocytes and it inhibits bone formation by
osteoblasts.[15][16][17]
Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass,
sclerosteosis and
van Buchem disease.[9]
van Buchem disease is an autosomal recessive skeletal disease characterized by bone overgrowth.[25] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[25][26] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and
diaphyses of long bones and bone formation occurs throughout life.[25] It is a very rare condition with about 30 known cases in 2002.[25] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[25] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[27] In the late 1990s, scientists at the company
Chiroscience and the
University of Cape Town determined that a "single mutation" in the gene was responsible for the disorder.[28]
An antibody for sclerostin is being developed because of the protein's specificity to bone.[15] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[29][30] In a
Phase I study, a single dose of anti-sclerostin
antibody from
Amgen (
Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated.[31] In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than
bisphosphonate and
teriparatide treatment; it had mild injection side effects.[16][32] A Phase II trial of a monoclonal human antibody to sclerostin from
Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group.[33] In a
Phase III trial, one year of Romosozumab treatment in post-menopausal women reduced the risk of vertebral fractures compared to the placebo group. It also increased the bone mineral density in the lumbar spine (13.3% versus 0.0%), femoral neck (5.2% versus −0.7%) and total hip (6.8% versus 0.0%) compared to the placebo group. Adverse events were balanced between the groups.[34] Sclerostin has significance within the field of dentistry[35] and regenerative strategies which target sclerostin are in development.[36] In April 2019, the
Food and Drug Administration approved Romosozumab for use in women with a very high risk of
osteoporotic fracture.[37] It was also approved for use in Japan[38] and the European Union in 2019.[39]
^Hernandez P, Whitty C, John Wardale R, Henson FM (April 2014). "New insights into the location and form of sclerostin". Biochemical and Biophysical Research Communications. 446 (4): 1108–13.
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10.1016/j.bbrc.2014.03.079.
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^Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (February 2009). "NMR structure of the Wnt modulator protein Sclerostin". Biochemical and Biophysical Research Communications. 380 (1): 160–5.
doi:
10.1016/j.bbrc.2009.01.062.
PMID19166819.
^
abVan Bezooijen, R. L.; Papapoulos, S. E.; Hamdy, N. A.; Ten Dijke, P.; Löwik, C. W. (2005). "Control of bone formation by osteocytes? Lessons from the rare skeletal disorders sclerosteosis and van Buchem disease". BoneKEy-Osteovision. 2 (12): 33–38.
doi:
10.1138/20050189.
^Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, et al. (April 2009). "Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis". Journal of Bone and Mineral Research. 24 (4): 578–88.
doi:
10.1359/jbmr.081206.
PMID19049336.
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Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, et al. (June 2002). "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population". American Journal of Medical Genetics. 110 (2): 144–52.
doi:
10.1002/ajmg.10401.
PMID12116252.
Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, et al. (October 2002). "Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms". Bone. 31 (4): 515–9.
doi:
10.1016/S8756-3282(02)00844-X.
PMID12398949.
Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA (October 2004). "Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation". Bone. 35 (4): 828–35.
doi:
10.1016/j.bone.2004.05.023.
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