Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
3  structures 45  species 0  interactions 114  sequences 3  architectures

Family: Sclerostin (PF05463)

Summary: Sclerostin (SOST)

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Sclerostin". More...

Sclerostin Edit Wikipedia article

Sclerostin

NMR structure of mouse sclerostin.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SOST; CDD; VBCH
External IDs OMIM605740 MGI1921749 HomoloGene11542 GeneCards: SOST Gene
Orthologs
Species Human Mouse
Entrez 50964 74499
Ensembl ENSG00000167941 ENSMUSG00000001494
UniProt Q9BQB4 Q99P68
RefSeq (mRNA) NM_025237 NM_024449
RefSeq (protein) NP_079513 NP_077769
Location (UCSC) Chr 17:
41.83 – 41.84 Mb
Chr 11:
101.96 – 101.97 Mb
PubMed search [1] [2]
Sclerostin
Identifiers
Symbol Sclerostin
Pfam PF05463
InterPro IPR008835

Sclerostin is a protein that in humans is encoded by the SOST gene.[2][3]

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.[4]

Structure[edit]

The sclerostin protein, with a length of 213 residues, has a dssp secondary structure that is 28% beta sheet (6 strands; 32 residues).[1]

Function[edit]

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[5] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[6] More recently sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[7][8] The inhibition of the Wnt pathway leads to decreased bone formation.[7] 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.[9][10] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[11][12][13]

Sclerostin production by osteocytes is inhibited by parathyroid hormone,[13][14] mechanical loading[15] and cytokines including prostaglandin E2,[16] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[17] Sclerostin production is increased by calcitonin.[18] Thus, osteoblast activity is self regulated by a negative feedback system.[19]

Clinical significance[edit]

Mutations in the gene sclerostin are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.[5] Sclerosteosis is an autosomal recessive disorder characterized by bone overgrowth. It was first described in 1958[20][21] but given the current name in 1967.[22] Excessive bone formation is most prominent in the skull, mandible and tubular bones.[20] It can cause facial distortion and syndactyly.[20] Increased intracranial pressure can cause sudden death in patients.[20] 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.[20]

van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth.[22] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[22][23] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.[22] It is a very rare condition with about 30 known cases in 2002.[22] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[22] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[20]

An antibody for sclerostin is being developed because of the protein’s specificity to bone.[11] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[24][25] 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.[26] 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.[12][27] It is expected to be on the market in 2017 and is predicted to be the gold standard in osteoporosis treatment by 2021.[28] In addition, OsteoGeneX is developing small molecule inhibitors of sclerostin.[29]

References[edit]

  1. ^ a b 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ "Entrez Gene: SOST sclerosteosis". 
  5. ^ a b 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.  edit
  6. ^ 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. 
  7. ^ a b 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ a b Bonewald LF (February 2011). "The amazing osteocyte". J. Bone Miner. Res. 26 (2): 229–38. doi:10.1002/jbmr.320. PMC 3179345. PMID 21254230. 
  12. ^ a b 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. 
  13. ^ a b 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ Genetos DC, Yellowley CE, Loots GG (March 2011). "Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression". PLoS One 16 (6): e17772. doi:10.1371/journal.pone.0017772. PMID 21436889. 
  17. ^ Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, Constable MJ, Nicholson GC, Zhang JG, Nicola NA, Gillespie MT, Martin TJ, Sims NA (February 2010). "Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice.". Journal of Clinical Investigation 120 (2): 582–92. doi:10.1172/JCI40568. PMID 20051625. 
  18. ^ Gooi JH, Pompolo S, Karsdal MA, Kulkarni NH, Kalajzic I, McAhren SH, Han B, Onyia JE, Ho PW, Gillespie MT, Walsh NC, Chia LY, Quinn JM, Martin TJ, Sims NA (February 2010). "Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes.". Bone 46 (6): 1486–97. doi:10.1016/j.bone.2010.02.018. PMID 20051625. 
  19. ^ http://users.telenet.be/zeldzame.ziekten/List.o/Pmenoposteo.htm
  20. ^ a b c d e f 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, A. F.; Hill, S.; Bueno, M.; Ramos, F. J.; Tacconi, P.; Dikkers, F. G.; Stratakis, C.; Lindpaintner, K.; Vickery, B.; Foernzler, D.; Van Hul, W. (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.  edit
  21. ^ 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.  edit
  22. ^ a b c d e f Balemans, W.; Patel, N.; Ebeling, M.; Van Hul, E.; Wuyts, W.; Lacza, C.; Dioszegi, M.; Dikkers, F. G.; Hildering, P.; Willems, P. J.; Verheij, J. B.; Lindpaintner, K.; Vickery, B.; Foernzler, D.; Van Hul, W. (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.  edit
  23. ^ 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.  edit
  24. ^ Li, X.; Ominsky, M. S.; Warmington, K. S.; Morony, S.; Gong, J.; Cao, J.; Gao, Y.; Shalhoub, V.; Tipton, B.; Haldankar, R.; Chen, Q.; Winters, A.; Boone, T.; Geng, Z.; Niu, Q. T.; Ke, H. Z.; Kostenuik, P. J.; Simonet, W. S.; Lacey, D. L.; Paszty, C. (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.  edit
  25. ^ Ominsky, M. S.; Vlasseros, F.; Jolette, J.; Smith, S. Y.; Stouch, B.; Doellgast, G.; Gong, J.; Gao, Y.; Cao, J.; Graham, K.; Tipton, B.; Cai, J.; Deshpande, R.; Zhou, L.; Hale, M. D.; Lightwood, D. J.; Henry, A. J.; Popplewell, A. G.; Moore, A. R.; Robinson, M. K.; Lacey, D. L.; Simonet, W. S.; Paszty, C. (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.  edit
  26. ^ 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.  edit
  27. ^ Reid, I. R. (2012). "Osteoporosis treatment at ASBMR 2012". IBMS BoneKEy 9. doi:10.1038/bonekey.2012.245.  edit
  28. ^ "For Osteoporosis and Osteopenia, Clinical Data and Thought Leaders' Opinions Indicate that AMG-785/CDP-7851 and Odanacatib Have Advantages Over Alendronate". PR Newswire. 2013-04-04. Retrieved 2013-04-20. 
  29. ^ 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[edit]

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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 [1].

Literature references

  1. 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

  2. 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 IPR008835

This 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].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Pfam Clan

This family is a member of clan Cystine-knot (CL0079), which contains the following 9 members:

Coagulin Cys_knot DAN Hormone_6 NGF Noggin PDGF Sclerostin TGF_beta

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(4)
Full
(114)
Representative proteomes NCBI
(111)
Meta
(0)
RP15
(6)
RP35
(11)
RP55
(23)
RP75
(56)
Jalview View  View  View  View  View  View  View   
HTML View  View  View  View  View  View     
PP/heatmap 1 View  View  View  View  View     
Pfam viewer View  View             

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(4)
Full
(114)
Representative proteomes NCBI
(111)
Meta
(0)
RP15
(6)
RP35
(11)
RP55
(23)
RP75
(56)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(4)
Full
(114)
Representative proteomes NCBI
(111)
Meta
(0)
RP15
(6)
RP35
(11)
RP55
(23)
RP75
(56)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_16740 (release 8.0)
Previous IDs: none
Type: Family
Author: Moxon SJ
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 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 21.4 20.7
Noise cut-off 20.5 19.7
Model length: 198
Family (HMM) version: 6
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Show

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Loading...

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.

Structures

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...