Sclerostin Explained

Sclerostin is a protein that in humans is encoded by the SOST gene.[1] It 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,[2] and has anti-anabolic effects on bone formation.[3]

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).[4]

Function

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] The inhibition of the Wnt pathway leads to decreased bone formation.[8] 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] estrogen[16] and cytokines including prostaglandin E2,[17] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[18] Sclerostin production is increased by calcitonin.[19] Thus, osteoblast activity is self regulated by a negative feedback system.[20]

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.[5]

van Buchem disease is an autosomal recessive skeletal disease characterized by bone overgrowth.[21] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[21] [22] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.[21] It is a very rare condition with about 30 known cases in 2002.[21] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[21] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[23] 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.[24]

Sclerostin antibody

See main article: Romosozumab.

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.[25] [26] 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.[27] 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] [28] 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.[29] 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.[30] Sclerostin has significance within the field of dentistry[31] and regenerative strategies which target sclerostin are in development.[32] In April 2019, the Food and Drug Administration approved Romosozumab for use in women with a very high risk of osteoporotic fracture.[33] It was also approved for use in Japan[34] and the European Union in 2019.[35]

Further reading

External links

Notes and References

  1. 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 . 6 . 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 . March 2001 . 11179006 . 1274471 . 10.1086/318811 .
  2. Hernandez P, Whitty C, John Wardale R, Henson FM . New insights into the location and form of sclerostin . Biochemical and Biophysical Research Communications . 446 . 4 . 1108–13 . April 2014 . 24667598 . 10.1016/j.bbrc.2014.03.079 .
  3. Web site: Entrez Gene: SOST sclerosteosis.
  4. Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD . NMR structure of the Wnt modulator protein Sclerostin . Biochemical and Biophysical Research Communications . 380 . 1 . 160–5 . February 2009 . 19166819 . 10.1016/j.bbrc.2009.01.062 .
  5. Van Bezooijen . R. L. . Papapoulos . S. E. . Hamdy . N. A. . Ten Dijke . P. . Löwik . C. W. . Control of bone formation by osteocytes? Lessons from the rare skeletal disorders sclerosteosis and van Buchem disease . 10.1138/20050189 . BoneKEy-Osteovision . 2 . 12 . 33–38 . 2005 .
  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 . 6 . Osteocyte control of bone formation via sclerostin, a novel BMP antagonist . The EMBO Journal . 22 . 23 . 6267–76 . December 2003 . 14633986 . 291840 . 10.1093/emboj/cdg599 .
  7. Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R . 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 . November 2006 . 17002572 . 10.1359/jbmr.060810 . 28614850 . free .
  8. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D . 6 . Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling . The Journal of Biological Chemistry . 280 . 20 . 19883–7 . May 2005 . 15778503 . 10.1074/jbc.M413274200 . free.
  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 . 6 . 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 . January 2007 . 17032150 . 10.1359/jbmr.061002 . 9235535 . free .
  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 . 6 . Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways . The Journal of Biological Chemistry . 285 . 53 . 41614–26 . December 2010 . 20952383 . 3009889 . 10.1074/jbc.M110.153890 . free .
  11. Bonewald LF . The amazing osteocyte . Journal of Bone and Mineral Research . 26 . 2 . 229–38 . February 2011 . 21254230 . 3179345 . 10.1002/jbmr.320 .
  12. Burgers TA, Williams BO . Regulation of Wnt/β-catenin signaling within and from osteocytes . Bone . 54 . 2 . 244–9 . June 2013 . 23470835 . 3652284 . 10.1016/j.bone.2013.02.022 .
  13. Bellido T, Saini V, Pajevic PD . Effects of PTH on osteocyte function . Bone . 54 . 2 . 250–7 . June 2013 . 23017659 . 3552098 . 10.1016/j.bone.2012.09.016 .
  14. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, Manolagas SC, Jilka RL . 6 . 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 . November 2005 . 16081646 . 10.1210/en.2005-0239 . free .
  15. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH . 6 . Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin . The Journal of Biological Chemistry . 283 . 9 . 5866–75 . February 2008 . 18089564 . 10.1074/jbc.M705092200 . free .
  16. Natasha M. . Appelman-Dijkstra . Socrates E. . Papapoulos . 2015 . Modulating Bone Resorption and Bone Formation in Opposite Directions in the Treatment of Postmenopausal Osteoporosis . 26056029 . 10.1007/s40265-015-0417-7 . 75 . 10 . 1049–1058 . Drugs. 4498277 .
  17. Genetos DC, Yellowley CE, Loots GG . Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression . PLOS ONE . 6 . 3 . e17772 . March 2011 . 21436889 . 3059227 . 10.1371/journal.pone.0017772 . 2011PLoSO...617772G . free .
  18. 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 . 6 . 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 . February 2010 . 20051625 . 2810087 . 10.1172/JCI40568 .
  19. 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 . 6 . Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes . Bone . 46 . 6 . 1486–97 . June 2010 . 20188226 . 10.1016/j.bone.2010.02.018 . 11343/52365 . free .
  20. Web site: Postmenopauzale Osteoporose.
  21. 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 . 6 . 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 . February 2002 . 11836356 . 1735035 . 10.1136/jmg.39.2.91 .
  22. Fosmoe RJ, Holm RS, Hildreth RC . Van Buchem's disease (hyperostosis corticalis generalisata familiaris). A case report . Radiology . 90 . 4 . 771–4 . April 1968 . 4867898 . 10.1148/90.4.771 .
  23. 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 . 6 . Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST) . Human Molecular Genetics . 10 . 5 . 537–43 . March 2001 . 11181578 . 10.1093/hmg/10.5.537 . free .
  24. News: Scientists find 'bone mass gene' in South Africans suffering from inherited disease. 26 May 1999. Oshkosh Northwestern. 24 December 2018. Associated Press. Oshkosh, Wisconsin. B5. Newspapers.com.
  25. 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 . 6 . 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 . April 2009 . 19049336 . 10.1359/jbmr.081206 . 1012895 .
  26. 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 . 6 . 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 . May 2010 . 20200929 . 10.1002/jbmr.14 . 206003762 . free .
  27. Padhi D, Jang G, Stouch B, Fang L, Posvar E . Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody . Journal of Bone and Mineral Research . 26 . 1 . 19–26 . January 2011 . 20593411 . 10.1002/jbmr.173 . 38080680 . free .
  28. Reid . I. R. . Osteoporosis treatment at ASBMR 2012 . IBMS BoneKEy . 9 . 2012 . 10.1038/bonekey.2012.245 .
  29. Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, Myers SL . 6 . 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 . February 2015 . 25196993 . 10.1002/jbmr.2351 . 25584452 . free .
  30. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, Hofbauer LC, Lau E, Lewiecki EM, Miyauchi A, Zerbini CA, Milmont CE, Chen L, Maddox J, Meisner PD, Libanati C, Grauer A . 6 . Romosozumab Treatment in Postmenopausal Women with Osteoporosis . The New England Journal of Medicine . 375 . 16 . 1532–1543 . October 2016 . 27641143 . 10.1056/NEJMoa1607948 . free .
  31. Samiei M, Janjić K, Cvikl B, Moritz A, Agis H . The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines . F1000Research . 8 . 128 . January 2019 . 31031968 . 6468704 . 10.12688/f1000research.17801.1 . free .
  32. Taut AD, Jin Q, Chung JH, Galindo-Moreno P, Yi ES, Sugai JV, Ke HZ, Liu M, Giannobile WV . 6 . Sclerostin antibody stimulates bone regeneration after experimental periodontitis . Journal of Bone and Mineral Research . 28 . 11 . 2347–56 . November 2013 . 23712325 . 10.1002/jbmr.1984 . 551897 . free .
  33. Web site: FDA approves romosozumab for osteoporosis. April 9, 2019. www.healio.com. en. 2019-05-11.
  34. Kaplon H, Muralidharan M, Schneider Z, Reichert JM . Antibodies to watch in 2020 . mAbs . 12 . 1 . 1703531 . 2020 . 31847708 . 6973335 . 10.1080/19420862.2019.1703531 .
  35. News: EC approves treatment for severe osteoporosis postmenopausal women . Victoria Rees . European Pharmaceutical Review . 13 December 2019 . 27 February 2020.

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