Sclerostin

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For other uses, see SOST (disambiguation).
Sclerostin
2KD3.png
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. PMC 3552098. 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 20188226. 
  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]