Summary: Sclerostin (SOST)
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Sclerostin Edit Wikipedia article
NMR structure of mouse sclerostin.
Sclerostin is a secreted glycoprotein with a C-terminal cysteine 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 by the osteocyte and has anti-anabolic effects on bone formation.
Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans, was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist. More recently sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway. The inhibition of the Wnt pathway leads to decreased 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 signaling, but not BMP signaling pathways. Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.
Sclerostin production by osteocytes is inhibited by parathyroid hormone, mechanical loading and cytokines including oncostatin M, cardiotrophin-1 and leukemia inhibitory factor. Sclerostin production is increased by calcitonin. Thus, osteoblast activity is self regulated by a negative feedback system.
 Clinical significance
Mutations in the gene sclerostin are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease. Sclerosteosis is an autosomal recessive disorder characterized by bone overgrowth. It was first described in 1958 but given the current name in 1967. Excessive bone formation is most prominent in the skull, mandible and tubular bones. It can cause facial distortion and syndactyly. Increased intracranial pressure can cause sudden death in patients. It is a rare disorder that is most prominent in the Afrikaner population in South Africa (40 patients), but there have also been cases of American and Brazilian families.
van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth. It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968. Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life. It is a very rare condition with about 30 known cases in 2002. In 1967 van Buchem characterized the disease in 15 patients of Dutch origin. Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.
An antibody for sclerostin is being developed because of the protein’s specificity to bone. Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys. In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (AMG 785) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated. 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. It is expected to be on the market in 2017 and is predicted to be the gold standard in osteoporosis treatment by 2021. In addition, OsteoGeneX is developing small molecule inhibitors of sclerostin.
- PDB 2KD3; Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (February 2009). "NMR structure of the Wnt modulator protein Sclerostin". Biochem. Biophys. Res. Commun. 380 (1): 160–5. doi:10.1016/j.bbrc.2009.01.062. PMID 19166819.
- Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (Feb 2001). "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein". Am J Hum Genet 68 (3): 577–89. doi:10.1086/318811. PMC 1274471. PMID 11179006.
- Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Feb 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Hum Mol Genet 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
- "Entrez Gene: SOST sclerosteosis".
- Van 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. doi:10.1138/20050189.
- Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (December 2003). "Osteocyte control of bone formation via sclerostin, a novel BMP antagonist". EMBO J. 22 (23): 6267–76. doi:10.1093/emboj/cdg599. PMC 291840. PMID 14633986.
- Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (May 2005). "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling". J. Biol. Chem. 280 (20): 19883–7. doi:10.1074/jbc.M413274200. PMID 15778503.
- Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (November 2006). "Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity". J. Bone Miner. Res. 21 (11): 1738–49. doi:10.1359/jbmr.060810. PMID 17002572.
- van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P, Löwik CW (January 2007). "Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation". J. Bone Miner. Res. 22 (1): 19–28. doi:10.1359/jbmr.061002. PMID 17032150.
- Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, Hatsell S, Economides AN, Mueller TD, Löwik CW, ten Dijke P (December 2010). "Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways". J. Biol. Chem. 285 (53): 41614–26. doi:10.1074/jbc.M110.153890. PMID 20952383.
- Bonewald LF (February 2011). "The amazing osteocyte". J. Bone Miner. Res. 26 (2): 229–38. doi:10.1002/jbmr.320. PMC 3179345. PMID 21254230.
- Burgers TA, Williams BO (June 2013). "Regulation of Wnt/β-catenin signaling within and from osteocytes". Bone 54 (2): 244–9. doi:10.1016/j.bone.2013.02.022. PMID 23470835.
- Bellido T, Saini V, Pajevic PD (June 2013). "Effects of PTH on osteocyte function". Bone 54 (2): 250–7. doi:10.1016/j.bone.2012.09.016. PMID 23017659.
- Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, Manolagas SC, Jilka RL (November 2005). "Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis". Endocrinology 146 (11): 4577–83. doi:10.1210/en.2005-0239. PMID 16081646.
- Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (February 2008). "Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin". J. Biol. Chem. 283 (9): 5866–75. doi:10.1074/jbc.M705092200. PMID 18089564.
- Balemans, W.; Ebeling, M.; Patel, N.; Van Hul, E.; Olson, P.; Dioszegi, M.; Lacza, C.; Wuyts, W. et al. (2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human molecular genetics 10 (5): 537–543. doi:10.1093/hmg/10.5.537. PMID 11181578.
- Truswell, A. S. (1958). "Osteopetrosis with syndactyly; a morphological variant of Albers-Schönberg's disease". The Journal of bone and joint surgery. British volume 40–B (2): 209–218. PMID 13539104.
- Balemans, W.; Patel, N.; Ebeling, M.; Van Hul, E.; Wuyts, W.; Lacza, C.; Dioszegi, M.; Dikkers, F. G. et al. (2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease". Journal of medical genetics 39 (2): 91–97. doi:10.1136/jmg.39.2.91. PMC 1735035. PMID 11836356.
- Fosmoe, R. J.; Holm, R. S.; Hildreth, R. C. (1968). "Van Buchem's disease (hyperostosis corticalis generalisata familiaris). A case report". Radiology 90 (4): 771–774. PMID 4867898.
- Li, X.; Ominsky, M. S.; Warmington, K. S.; Morony, S.; Gong, J.; Cao, J.; Gao, Y.; Shalhoub, V. et al. (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): 578–588. doi:10.1359/jbmr.081206. PMID 19049336.
- Ominsky, M. S.; Vlasseros, F.; Jolette, J.; Smith, S. Y.; Stouch, B.; Doellgast, G.; Gong, J.; Gao, Y. et al. (2010). "Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength". Journal of Bone and Mineral Research 25 (5): 948–959. doi:10.1002/jbmr.14. PMID 20200929.
- Padhi, D.; Jang, G.; Stouch, B.; Fang, L.; Posvar, E. (2011). "Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody". Journal of Bone and Mineral Research 26 (1): 19–26. doi:10.1002/jbmr.173. PMID 20593411.
- Reid, I. R. (2012). "Osteoporosis treatment at ASBMR 2012". IBMS BoneKEy 9. doi:10.1038/bonekey.2012.245.
- "For Osteoporosis and Osteopenia, Clinical Data and Thought Leaders' Opinions Indicate that AMG-785/CDP-7851 and Odanacatib Have Advantages Over Alendronate". PR Newswire. 2013-4-4. Retrieved 2013-4-20.
- Rey JP, Ellies DL (January 2010). "Wnt modulators in the biotech pipeline". Dev. Dyn. 239 (1): 102–14. doi:10.1002/dvdy.22181. PMC 3111251. PMID 20014100.
 Further reading
- Balemans W, Van Hul W (2007). "Human genetics of SOST.". Journal of musculoskeletal & neuronal interactions 6 (4): 355–6. PMID 17185822.
- Balemans W, Patel N, Ebeling M, et al. (2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.". J. Med. Genet. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC 1735035. PMID 11836356.
- Staehling-Hampton K, Proll S, Paeper BW, et al. (2002). "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population.". Am. J. Med. Genet. 110 (2): 144–52. doi:10.1002/ajmg.10401. PMID 12116252.
- Balemans W, Foernzler D, Parsons C, et al. (2003). "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. PMID 12398949.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Clark HF, Gurney AL, Abaya E, et al. (2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
- Sevetson B, Taylor S, Pan Y (2004). "Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST).". J. Biol. Chem. 279 (14): 13849–58. doi:10.1074/jbc.M306249200. PMID 14739291.
- van Bezooijen RL, Roelen BA, Visser A, et al. (2004). "Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist.". J. Exp. Med. 199 (6): 805–14. doi:10.1084/jem.20031454. PMC 2212719. PMID 15024046.
- Winkler DG, Yu C, Geoghegan JC, et al. (2004). "Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex.". J. Biol. Chem. 279 (35): 36293–8. doi:10.1074/jbc.M400521200. PMID 15199066.
- Zhang Z, Henzel WJ (2005). "Signal peptide prediction based on analysis of experimentally verified cleavage sites.". Protein Sci. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
- Sutherland MK, Geoghegan JC, Yu C, et al. (2005). "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. PMID 15454089.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Uitterlinden AG, Arp PP, Paeper BW, et al. (2005). "Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites.". Am. J. Hum. Genet. 75 (6): 1032–45. doi:10.1086/426458. PMC 1182139. PMID 15514891.
- Winkler DG, Sutherland MS, Ojala E, et al. (2005). "Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins.". J. Biol. Chem. 280 (4): 2498–502. doi:10.1074/jbc.M400524200. PMID 15545262.
- Poole KE, van Bezooijen RL, Loveridge N, et al. (2006). "Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation.". FASEB J. 19 (13): 1842–4. doi:10.1096/fj.05-4221fje. PMID 16123173.
- Gardner JC, van Bezooijen RL, Mervis B, et al. (2006). "Bone mineral density in sclerosteosis; affected individuals and gene carriers.". J. Clin. Endocrinol. Metab. 90 (12): 6392–5. doi:10.1210/jc.2005-1235. PMID 16189254.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Sclerostin (SOST) Provide feedback
This family contains several mammalian sclerostin (SOST) proteins. SOST is thought to suppress bone formation. Mutations of the SOST gene lead to sclerosteosis, a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterised by a generalised 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 .
Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W; , Hum Mol Genet 2001;10:537-543.: Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). PUBMED:11181578 EPMC:11181578
Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J; , Am J Hum Genet 2001;68:577-589.: Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. PUBMED:11179006 EPMC:11179006
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR008835This sclerostin family consists of sclerostin and sclerostin domain-containing protein 1. Sclerostin (SOST) is thought to suppress bone formation. Mutations of the SOST gene lead to sclerosteosis, a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterised by a generalised 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 [PUBMED:11181578]. Sclerostin domain-containing protein 1, also known as USAG1, is a bone morphogenetic protein antagonist [PUBMED:15020244].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||extracellular space (GO:0005615)|
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|Seed source:||Pfam-B_16740 (release 8.0)|
|Number in seed:||4|
|Number in full:||114|
|Average length of the domain:||177.90 aa|
|Average identity of full alignment:||50 %|
|Average coverage of the sequence by the domain:||95.52 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||6|
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Sclerostin domain has been found. There are 3 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...