Sclerostin

SOST
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSOST, CDD, SOST1, VBCH, DAND6, sclerostin
External IDsOMIM: 605740 MGI: 1921749 HomoloGene: 11542 GeneCards: SOST
Gene location (Human)
Chr.Chromosome 17 (human)[1]
Band17q21.31Start43,753,731 bp[1]
End43,758,788 bp[1]
Orthologs
SpeciesHumanMouse
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: 43.75 – 43.76 MbChr 11: 101.96 – 101.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Sclerostin
Identifiers
Symbol Sclerostin
Pfam PF05463
InterPro IPR008835

Sclerostin is a protein that in humans is encoded by the SOST gene.[5][6]

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 primarily by the osteocyte but is also expressed in other tissues,[7] and has anti-anabolic effects on bone formation.[8]

Structure

The sclerostin protein, with a length of 213 residues, has a secondary structure that has been determined by protein NMR to be 28% beta sheet (6 strands; 32 residues).[9]

Function

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[10] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[11] More recently sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[12][13] The inhibition of the Wnt pathway leads to decreased bone formation.[12] 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.[14][15] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[16][17][18]

Sclerostin production by osteocytes is inhibited by parathyroid hormone,[18][19] mechanical loading[20] and cytokines including prostaglandin E2,[21] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[22] Sclerostin production is increased by calcitonin.[23] Thus, osteoblast activity is self regulated by a negative feedback system.[24]

Clinical significance

Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.[10]

van Buchem disease is also 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]

An antibody for sclerostin is being developed because of the protein’s specificity to bone.[16] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[28][29] 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.[30] 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.[17][31] 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.[32] 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.[33]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000167941 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001494 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ 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 (Mar 2001). "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein". American Journal of Human Genetics. 68 (3): 577–89. doi:10.1086/318811. PMC 1274471. PMID 11179006.
  6. ↑ 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 (Mar 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics. 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
  7. ↑ Hernandez, Paula; Whitty, Ciara; John Wardale, R.; Henson, Frances M.D. (2014). "New insights into the location and form of sclerostin". Biochemical and Biophysical Research Communications. 446 (4): 1108–1113. doi:10.1016/j.bbrc.2014.03.079. PMID 24667598.
  8. ↑ "Entrez Gene: SOST sclerosteosis".
  9. ↑ Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (Feb 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.
  10. 1 2 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): 33–38. doi:10.1138/20050189.
  11. ↑ 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 (Dec 2003). "Osteocyte control of bone formation via sclerostin, a novel BMP antagonist". The EMBO Journal. 22 (23): 6267–76. doi:10.1093/emboj/cdg599. PMC 291840. PMID 14633986.
  12. 1 2 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". The Journal of Biological Chemistry. 280 (20): 19883–7. doi:10.1074/jbc.M413274200. PMID 15778503.
  13. ↑ Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (Nov 2006). "Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity". Journal of Bone and Mineral Research. 21 (11): 1738–49. doi:10.1359/jbmr.060810. PMID 17002572.
  14. ↑ 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 (Jan 2007). "Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation". Journal of Bone and Mineral Research. 22 (1): 19–28. doi:10.1359/jbmr.061002. PMID 17032150.
  15. ↑ 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 (Dec 2010). "Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways". The Journal of Biological Chemistry. 285 (53): 41614–26. doi:10.1074/jbc.M110.153890. PMC 3009889. PMID 20952383.
  16. 1 2 Bonewald LF (Feb 2011). "The amazing osteocyte". Journal of Bone and Mineral Research. 26 (2): 229–38. doi:10.1002/jbmr.320. PMC 3179345. PMID 21254230.
  17. 1 2 Burgers TA, Williams BO (Jun 2013). "Regulation of Wnt/β-catenin signaling within and from osteocytes". Bone. 54 (2): 244–9. doi:10.1016/j.bone.2013.02.022. PMC 3652284. PMID 23470835.
  18. 1 2 Bellido T, Saini V, Pajevic PD (Jun 2013). "Effects of PTH on osteocyte function". Bone. 54 (2): 250–7. doi:10.1016/j.bone.2012.09.016. PMC 3552098. PMID 23017659.
  19. ↑ Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, Manolagas SC, Jilka RL (Nov 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.
  20. ↑ Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (Feb 2008). "Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin". The Journal of Biological Chemistry. 283 (9): 5866–75. doi:10.1074/jbc.M705092200. PMID 18089564.
  21. ↑ Genetos DC, Yellowley CE, Loots GG (March 2011). "Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression". PLOS ONE. 6 (3): e17772. doi:10.1371/journal.pone.0017772. PMC 3059227. PMID 21436889.
  22. ↑ 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 (Feb 2010). "Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice". The Journal of Clinical Investigation. 120 (2): 582–92. doi:10.1172/JCI40568. PMC 2810087. PMID 20051625.
  23. ↑ 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 (Jun 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.
  24. ↑ http://users.telenet.be/zeldzame.ziekten/List.o/Pmenoposteo.htm
  25. 1 2 3 4 5 Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Feb 2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease". Journal of Medical Genetics. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC 1735035. PMID 11836356.
  26. ↑ Fosmoe RJ, Holm RS, Hildreth RC (Apr 1968). "Van Buchem's disease (hyperostosis corticalis generalisata familiaris). A case report". Radiology. 90 (4): 771–4. doi:10.1148/90.4.771. PMID 4867898.
  27. ↑ 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 (Mar 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics. 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
  28. ↑ Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (Apr 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. PMID 19049336.
  29. ↑ Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK, Lacey DL, Simonet WS, Paszty C (May 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): 948–59. doi:10.1002/jbmr.14. PMID 20200929.
  30. ↑ Padhi D, Jang G, Stouch B, Fang L, Posvar E (Jan 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.
  31. ↑ Reid, I. R. (2012). "Osteoporosis treatment at ASBMR 2012". IBMS BoneKEy. 9. doi:10.1038/bonekey.2012.245.
  32. ↑ Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, Myers SL (Feb 2015). "A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density". Journal of Bone and Mineral Research. 30 (2): 216–24. doi:10.1002/jbmr.2351. PMID 25196993.
  33. ↑ Cosman, et al. (2016). "Romosozumab Treatment in Postmenopausal Women with Osteoporosis". The New England Journal of Medicine. 375 (16): 1532–1543. doi:10.1056/NEJMoa1607948. PMID 27641143.

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, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Feb 2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease". Journal of Medical Genetics. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC 1735035. PMID 11836356.
  • Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, Gardner JC, Galas D, Schatzman RC, Beighton P, Papapoulos S, Hamersma H, Brunkow ME (Jun 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. PMID 12116252.
  • Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, Lindpaintner K, Ralston SH, Van Hul W (Oct 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. PMID 12398949.
  • Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (Oct 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
  • Sevetson B, Taylor S, Pan Y (Apr 2004). "Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST)". The Journal of Biological Chemistry. 279 (14): 13849–58. doi:10.1074/jbc.M306249200. PMID 14739291.
  • van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Löwik CW (Mar 2004). "Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist". The Journal of Experimental Medicine. 199 (6): 805–14. doi:10.1084/jem.20031454. PMC 2212719. PMID 15024046.
  • Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, Sutherland MK, Latham JA (Aug 2004). "Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex". The Journal of Biological Chemistry. 279 (35): 36293–8. doi:10.1074/jbc.M400521200. PMID 15199066.
  • Zhang Z, Henzel WJ (Oct 2004). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Science. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
  • Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA (Oct 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. PMID 15454089.
  • Uitterlinden AG, Arp PP, Paeper BW, Charmley P, Proll S, Rivadeneira F, Fang Y, van Meurs JB, Britschgi TB, Latham JA, Schatzman RC, Pols HA, Brunkow ME (Dec 2004). "Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites". American Journal of Human Genetics. 75 (6): 1032–45. doi:10.1086/426458. PMC 1182139. PMID 15514891.
  • Winkler DG, Sutherland MS, Ojala E, Turcott E, Geoghegan JC, Shpektor D, Skonier JE, Yu C, Latham JA (Jan 2005). "Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins". The Journal of Biological Chemistry. 280 (4): 2498–502. doi:10.1074/jbc.M400524200. PMID 15545262.
  • Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CW, Reeve J (Nov 2005). "Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation". FASEB Journal. 19 (13): 1842–4. doi:10.1096/fj.05-4221fje. PMID 16123173.
  • Gardner JC, van Bezooijen RL, Mervis B, Hamdy NA, Löwik CW, Hamersma H, Beighton P, Papapoulos SE (Dec 2005). "Bone mineral density in sclerosteosis; affected individuals and gene carriers". The Journal of Clinical Endocrinology and Metabolism. 90 (12): 6392–5. doi:10.1210/jc.2005-1235. PMID 16189254.
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