Sclerostin

Last updated
SOST
2KD3.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SOST , CDD, SOST1, VBCH, DAND6, sclerostin, Sclerostin
External IDs OMIM: 605740 MGI: 1921749 HomoloGene: 11542 GeneCards: SOST
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 Mb Chr 11: 101.85 – 101.86 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Sclerostin
Identifiers
SymbolSclerostin
Pfam PF05463
InterPro IPR008835
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Sclerostin is a protein that in humans is encoded by the SOST gene. [5] 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, [6] and has anti-anabolic effects on bone formation. [7]

Contents

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). [8]

Function

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans, [9] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist. [10] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway. [11] [12] The inhibition of the Wnt pathway leads to decreased bone formation. [11] 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. [13] [14] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts. [15] [16] [17]

Sclerostin production by osteocytes is inhibited by parathyroid hormone, [17] [18] mechanical loading, [19] estrogen [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. [9]

van Buchem disease is 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] 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. [28]

Sclerostin antibody

An antibody for sclerostin is being developed because of the protein's specificity to bone. [15] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys. [29] [30] 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. [31] 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. [16] [32] 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. [33] 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. [34] Sclerostin has significance within the field of dentistry [35] and regenerative strategies which target sclerostin are in development. [36] In April 2019, the Food and Drug Administration approved Romosozumab for use in women with a very high risk of osteoporotic fracture. [37] It was also approved for use in Japan [38] and the European Union in 2019. [39]

Related Research Articles

<span class="mw-page-title-main">Osteoblast</span> Cells secreting extracellular matrix

Osteoblasts are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function in groups of connected cells. Individual cells cannot make bone. A group of organized osteoblasts together with the bone made by a unit of cells is usually called the osteon.

<span class="mw-page-title-main">Bisphosphonate</span> Pharmaceutical drugs for preventing bone loss

Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they have two phosphonate groups. They are thus also called diphosphonates.

<span class="mw-page-title-main">Osteogenesis imperfecta</span> Group of genetic disorders that mainly affect the bones

Osteogenesis imperfecta, colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead, short stature, loose joints, hearing loss, breathing problems and problems with the teeth. Potentially life-threatening complications, all of which become more common in more severe OI, include: tearing (dissection) of the major arteries, such as the aorta; pulmonary valve insufficiency secondary to distortion of the ribcage; and basilar invagination.

<span class="mw-page-title-main">Osteocyte</span> Mature osteoblasts which helps in communication between cells and also in molecular synthesis

An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and have an average half life of 25 years. They are derived from osteoprogenitor cells, some of which differentiate into active osteoblasts. Osteoblasts/osteocytes develop in mesenchyme.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Osteocalcin</span> Mammalian protein found in Homo sapiens

Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein.

<span class="mw-page-title-main">Bone morphogenetic protein 7</span> Protein-coding gene in the species Homo sapiens

Bone morphogenetic protein 7 or BMP7 is a protein that in humans is encoded by the BMP7 gene.

<span class="mw-page-title-main">RANKL</span> Mammalian protein found in Homo sapiens

Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.

<span class="mw-page-title-main">Denosumab</span> Human monoclonal antibody

Denosumab is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

<span class="mw-page-title-main">GDF2</span> Protein-coding gene in the species Homo sapiens

Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily.

<span class="mw-page-title-main">GDF6</span> Protein-coding gene in the species Homo sapiens

Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.

<span class="mw-page-title-main">LRP5</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.

<span class="mw-page-title-main">LRP6</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

<span class="mw-page-title-main">Sp7 transcription factor</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp7, also called osterix (Osx), is a protein that in humans is encoded by the SP7 gene. It is a member of the Sp family of zinc-finger transcription factors It is highly conserved among bone-forming vertebrate species It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes. Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, a mouse embryo model with Sp7 expression knocked out had no formation of bone tissue. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. In addition there is significant genetic evidence for its role in diseases such as Osteogenesis imperfecta (OI).

Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.

Blosozumab binds SOST, a negative regulator of osteoblast activity. Blocking SOST activity can lead to increased bone density. Blosozaumab has been studied with regards to the treatment of osteoporosis in both men and postmenopausal women. Clinical trials with Blosozumab have shown the antibody to be well tolerated and effective in producing a bone anabolic effect.

Abaloparatide, sold under the brand name Tymlos among others, is a parathyroid hormone-related protein (PTHrP) analog medication used to treat osteoporosis. It is an anabolic agent.

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, but there have also been cases of American and Brazilian families.

A bone growth factor is a growth factor that stimulates the growth of bone tissue.

<span class="mw-page-title-main">Bone marrow adipose tissue</span>

Bone marrow adipose tissue (BMAT), sometimes referred to as marrow adipose tissue (MAT), is a type of fat deposit in bone marrow. It increases in states of low bone density -osteoporosis, anorexia nervosa/ caloric restriction, skeletal unweighting such as that which occurs in space travel, and anti-diabetes therapies. BMAT decreases in anaemia, leukaemia, and hypertensive heart failure; in response to hormones such as oestrogen, leptin, and growth hormone; with exercise-induced weight loss or bariatric surgery; in response to chronic cold exposure; and in response to pharmacological agents such as bisphosphonates, teriparatide, and metformin.

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:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. (March 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. ↑ Hernandez P, Whitty C, John Wardale R, Henson FM (April 2014). "New insights into the location and form of sclerostin". Biochemical and Biophysical Research Communications. 446 (4): 1108–13. doi:10.1016/j.bbrc.2014.03.079. PMID   24667598.
  7. ↑ "Entrez Gene: SOST sclerosteosis".
  8. ↑ Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (February 2009). "NMR structure of the Wnt modulator protein Sclerostin". Biochemical and Biophysical Research Communications. 380 (1): 160–5. doi:10.1016/j.bbrc.2009.01.062. PMID   19166819.
  9. 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.
  10. ↑ Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. (December 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.
  11. 1 2 Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. (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.
  12. ↑ 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". Journal of Bone and Mineral Research. 21 (11): 1738–49. doi: 10.1359/jbmr.060810 . PMID   17002572. S2CID   28614850.
  13. ↑ van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. (January 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. S2CID   9235535.
  14. ↑ Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, et al. (December 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.
  15. 1 2 Bonewald LF (February 2011). "The amazing osteocyte". Journal of Bone and Mineral Research. 26 (2): 229–38. doi:10.1002/jbmr.320. PMC   3179345 . PMID   21254230.
  16. 1 2 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. PMC   3652284 . PMID   23470835.
  17. 1 2 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.
  18. ↑ Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. (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.
  19. ↑ Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. (February 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.
  20. ↑ Appelman-Dijkstra, Natasha M.; Papapoulos, Socrates E. (2015). "Modulating Bone Resorption and Bone Formation in Opposite Directions in the Treatment of Postmenopausal Osteoporosis". Drugs. 75 (10): 1049–1058. doi:10.1007/s40265-015-0417-7. PMC   4498277 . PMID   26056029.
  21. ↑ Genetos DC, Yellowley CE, Loots GG (March 2011). "Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression". PLOS ONE. 6 (3): e17772. Bibcode:2011PLoSO...617772G. doi: 10.1371/journal.pone.0017772 . PMC   3059227 . PMID   21436889.
  22. ↑ Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, et al. (February 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, et al. (June 2010). "Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes" (PDF). Bone. 46 (6): 1486–97. doi:10.1016/j.bone.2010.02.018. hdl: 11343/52365 . PMID   20188226.
  24. ↑ "Postmenopauzale Osteoporose".
  25. 1 2 3 4 5 Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. (February 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 (April 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, et al. (March 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)" (PDF). Human Molecular Genetics. 10 (5): 537–43. doi: 10.1093/hmg/10.5.537 . PMID   11181578.
  28. ↑ "Scientists find 'bone mass gene' in South Africans suffering from inherited disease". Oshkosh Northwestern. Oshkosh, Wisconsin. Associated Press. 26 May 1999. p. B5. Retrieved 24 December 2018– via Newspapers.com.
  29. ↑ Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, et al. (April 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. S2CID   1012895.
  30. ↑ Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, et al. (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. S2CID   206003762.
  31. ↑ Padhi D, Jang G, Stouch B, Fang L, Posvar E (January 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. S2CID   38080680.
  32. ↑ Reid, I. R. (2012). "Osteoporosis treatment at ASBMR 2012". IBMS BoneKEy. 9. doi:10.1038/bonekey.2012.245.
  33. ↑ Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, et al. (February 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. S2CID   25584452.
  34. ↑ Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. (October 2016). "Romosozumab Treatment in Postmenopausal Women with Osteoporosis". The New England Journal of Medicine. 375 (16): 1532–1543. doi:10.1056/NEJMoa1607948. PMID   27641143.
  35. ↑ Samiei M, Janjić K, Cvikl B, Moritz A, Agis H (January 2019). "The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines". F1000Research. 8: 128. doi: 10.12688/f1000research.17801.1 . PMC   6468704 . PMID   31031968.
  36. ↑ Taut AD, Jin Q, Chung JH, Galindo-Moreno P, Yi ES, Sugai JV, et al. (November 2013). "Sclerostin antibody stimulates bone regeneration after experimental periodontitis" (PDF). Journal of Bone and Mineral Research. 28 (11): 2347–56. doi: 10.1002/jbmr.1984 . PMID   23712325. S2CID   551897.
  37. ↑ "FDA approves romosozumab for osteoporosis". www.healio.com. April 9, 2019. Retrieved 2019-05-11.
  38. ↑ Kaplon H, Muralidharan M, Schneider Z, Reichert JM (2020). "Antibodies to watch in 2020". mAbs. 12 (1): 1703531. doi:10.1080/19420862.2019.1703531. PMC   6973335 . PMID   31847708.
  39. ↑ Victoria Rees (13 December 2019). "EC approves treatment for severe osteoporosis postmenopausal women". European Pharmaceutical Review. Retrieved 27 February 2020.

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