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Sclerostin and skeletal health

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Abstract

Sclerostin is a cysteine-knot glycoprotein product of the SOST gene, predominately expressed by osteocytes, that is a regulator of osteoblastic bone formation. When sclerostin binds to its low-density lipoprotein receptor-related proteins 5 and 6 on the cell membrane of osteoblasts, it inhibits canonical Wnt/β-catenin signaling and reduces osteoblastic bone formation. Sclerostin was first identified in the study of two rare autosomal recessive disorders, sclerosteosis and van Buchem disease, which are associated with absent or reduced levels of sclerostin. Although homozygote patients with these disorders have serious adverse clinical consequences due to excessive bone growth, heterozygote patients have a normal phenotype, high bone mass, and very low risk of fractures. This has led to the concept that downregulation of sclerostin might be effective in the treatment of osteoporosis. Several humanized monoclonal antibodies to sclerostin, including romosozumab and blosozumab, are now in clinical development. Preliminary data show that these agents result in a transient increase in bone formation markers, a sustained decrease in bone resorption markers, and a robust increase in bone mineral density. If any of these agents are found to reduce fracture risk with a favorable safety profile, it will expand the options for osteoanabolic therapy for patients at high risk for fractures.

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References

  1. Nusse R, Varmus H. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31:99–109.

    Article  CAS  PubMed  Google Scholar 

  2. Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis. 2014;6(2):48–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Kim J, Liu X, Wang J, Chen X, Zhang H, Kim S, et al. Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis. 2013;5:13–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Ke H, Richards W, Li X, Ominsky M. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev. 2012;33:747–83.

    Article  CAS  PubMed  Google Scholar 

  5. Lewiecki E. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat Rev Rheumatol. 2011;7:631–8.

    Article  CAS  PubMed  Google Scholar 

  6. Goldring M. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012;4:269–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Krause C, Korchynskyi O, de Rooij K, et al. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. J Biol Chem. 2010;285(53):41614–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280(20):19883–7.

    Article  CAS  PubMed  Google Scholar 

  9. Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280(29):26770–5.

    Article  CAS  PubMed  Google Scholar 

  10. Van Bezooijen RL, Svensson JP, Eefting D, et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res. 2007;22(1):19–28.

    Article  PubMed  Google Scholar 

  11. Van Buchem FS, Hadders HN, Ubbens R. An uncommon familial systemic disease of the skeleton: hyperostosis corticalis generalisata familiaris. Acta Radiol. 1955;44(2):109–20.

    Article  Google Scholar 

  12. Truswell AS. Osteopetrosis with syndactyly; a morphological variant of albers-schonberg’s disease. J Bone Joint Surg (Br). 1958;40-B(2):209–18.

    CAS  Google Scholar 

  13. Costa AG, Bilezikian JP & Lewiecki EM. Update on romosozumab:a humanized monoclonal antibody to sclerostin. Expert Opin. Biol. Ther. 2014[Early Online].

  14. van Bezooijen R, Roelen B, Visser A, Van der Wee-Pals L, de Wilt E, Karperien M, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199:805–14.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest. 2009;119(4):837–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Kanis J. Assessment of osteoporosis at the primary health-care level. Technical report. World Health Organization Collaborating Centre for Metabolic Bone Diseases. 2007; Sheffield: University of Sheffield.

  17. Delmas PD, van de Langerijt L, Watts NB, Eastell R, Genant H, Grauer A, et al. Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone Miner Res Off J Am Soc Bone Miner Res. 2005;20(4):557–63.

    Article  Google Scholar 

  18. Foley KA, Foster SA, Meadows ES, Baser O, Long SR. Assessment of the clinical management of fragility fractures and implications for the new HEDIS osteoporosis measure. Med Care. 2007;45(9):902–6.

    Article  PubMed  Google Scholar 

  19. Roudier M, Li X, Niu Q, Pacheco E, Pretorius J, Graham K, et al. Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury. Arthritis Rheum. 2013;65:721–31.

    Article  CAS  PubMed  Google Scholar 

  20. Brunkow M, Gardner J, Van N, Paeper B, Kovacevich B, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68:577–89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Veverka V, Henry A, Slocombe P, Ventom A, Mulloy B, Muskett F, et al. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt mediated bone formation. J Biol Chem. 2009;284:10890–900.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Balemans W, Ebeling M, Patel N, Van H, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537–43.

    Article  CAS  PubMed  Google Scholar 

  23. Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, et al. Canonical Wnt signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem. 2005;280(39):33132–40.

    Article  CAS  PubMed  Google Scholar 

  24. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006;281(32):22429–33.

    Article  CAS  PubMed  Google Scholar 

  25. Bodine PVN, Komm BS. Wnt signaling and osteoblastogenesis. Rev Endocr Metab Disord. 2006;7(1–2):33–9.

    CAS  PubMed  Google Scholar 

  26. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883–7.

    Article  CAS  PubMed  Google Scholar 

  27. Baron R, Rawadi G. Targeting the Wnt/ beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43.

    Article  CAS  PubMed  Google Scholar 

  28. Li X, Ominsky M, Niu Q, Sun N, Daugherty B, D’Agostin D, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23:860–9.

    Article  PubMed  Google Scholar 

  29. Beighton P, Davidson J, Durr L, Hamersma H. Sclerosteosis – an autosomal recessive disorder. Clin Genet. 1977;11:1–7.

    Article  CAS  PubMed  Google Scholar 

  30. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet. 2003;63:192–7.

    Article  CAS  PubMed  Google Scholar 

  31. Gardner J, van Bezooijen R, Mervis B, Hamdy N, Lowik C, Hamersma H, et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab. 2005;90:6392–5.

    Article  CAS  PubMed  Google Scholar 

  32. Van Lierop A, Hamdy N, Hamersma H, van Bezooijen R, Power J, Loveridge N, et al. Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. J Bone Miner Res. 2011;26:2804–11.

    Article  PubMed  Google Scholar 

  33. Wergedal J, Veskovic K, Hellan M, Nyght C, Balemans W, Libanati C, et al. Patients with Van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and greater derived polar moment of inertia than normal. J Clin Endocrinol Metab. 2003;88:5778–83.

    Article  CAS  PubMed  Google Scholar 

  34. Robling A, Niziolek P, Baldridge L, Condon K, Allen M, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/ sclerostin. J Biol Chem. 2008;283:5866–75.

    Article  CAS  PubMed  Google Scholar 

  35. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/betacatenin signaling. J Bone Miner Res. 2009;24:1651–61.

    Article  CAS  PubMed  Google Scholar 

  36. Kramer I, Loots G, Studer A, Keller H, Kneissel M. Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res. 2010;25:178–89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Lories R, Luyten F. The bone-cartilage unit in osteoarthritis. Nat Rev Rheumatol. 2011;7:43–9.

    Article  CAS  PubMed  Google Scholar 

  38. Luyten F, Tylzanowski P, Lories R. Wnt signaling and osteoarthritis. Bone. 2009;44:522–7.

    Article  CAS  PubMed  Google Scholar 

  39. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2009;24:12–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Zhu M, Chen M, Zuscik M, Wu Q, Wang Y, Rosier R, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58:2053–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Chan B, Fuller E, Russell A, Smith S, Smith M, Jackson M, et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthr Cartil. 2011;19:874–85.

    Article  CAS  PubMed  Google Scholar 

  42. Babcook J, Leslie K, Olsen O, Salmon R, Schrader J. A novel strategy for generating monoclonal antibodies from single, isolated lymphocytes producing antibodies of defined specificities. Proc Natl Acad Sci U S A. 1993;93(15):7843–8.

    Article  Google Scholar 

  43. Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res Off J Am Soc Bone Miner Res. 2010;25(5):948–59.

    Article  CAS  Google Scholar 

  44. Agholme F, Li X, Isaksson H, Ke HZ, Aspenberg P. Sclerostin antibody treatment enhances metaphyseal bone healing in rats. J Bone Miner Res Off J Am Soc Bone Miner Res. 2010;25(11):2412–8.

    Article  CAS  Google Scholar 

  45. Li X, Warmington KS, Niu QT, Asuncion FJ, Barrero M, Grisanti M, et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass and bone strength in aged male rats. J Bone Miner Res. 2010;25(12):2647–56.

    Article  PubMed  Google Scholar 

  46. Ominsky M, Samadfan R, Jolette J, Vlasseros F, Smith S, Kostenuik P, et al. Sclerostin monoclonal antibody stimulates bone formation and improves the strength and density of the fracture callus and lumbar spine in a primate fibular osteotomy model. J Bone Miner Res. 2009;24 Suppl 1:S89–90.

    Google Scholar 

  47. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26:19–26.

    Article  CAS  PubMed  Google Scholar 

  48. Wang W, Wang E, Balthasar J. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548–58.

    Article  CAS  PubMed  Google Scholar 

  49. McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370(5):412–20.

    Article  CAS  PubMed  Google Scholar 

  50. McClung MR, Chines A, Brown JP, Diez-Perez A, Resch H, Caminis J,Bolognese Ma, Goemaere S, Bone HG, Zanchetta JR, Maddox J, Rosen O, Bray S, Grauer A. Effects of 2 years of treatment with romosozumab followed by 1 year of denosumab or placebo in postmenopausal women with low bone mineral density. Presented in ASBMR Sep 2014.

  51. Whitmarsh T, Treece G, Gee A, Bolognese M, Brown JP, Goemaere S, Grauer A, Hanley D, Mautalen C, Recknor C, Yang Y, Libanati C, Poole K. Romosozumab and teriparatide effects on vertebral cortical mass, thickness, and density in postmenopausal women with low bone mineral density (BMD). Presented in ASBMR Sep 2014.

  52. Treece G, Gee A, Mayhew P, Poole K. High resolution cortical bone thickness measurement from clinical CT data. Med Image Anal. 2010;14(3):276–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. McColm J, Womack T, Hu L, Tang C, Chiang A. Blosozumab, a humanized monoclonal antibody against sclerostin, demonstrated anabolic effects on bone in postmenopausal women. J Bone Miner Res. 2012;27 Suppl 1:S9.

    Google Scholar 

  54. Benson, C., Robins, D., Recker, R., Alam, J., Chiang, A., Mitlak, B. et al. Effect of blosozumab on bone mineral density: results of a phase 2 study of postmenopausal women with low bone mineral density. Bone Abstracts. 2013; 1: OC5.3.

  55. Benson C, Chiang A, Hu L, Jahangir A, Mitlak B, Recker R, Robins D, Sowa H, Sipos A. Effect of blosozumab on bone mineral density: 52-week follow-up of a phase 2 study of postmenopausal women with low bone mineral density. Presented in ASBMR Sep 2014.

  56. Cornell CN. Internal fracture fixation in patients with osteoporosis. J Am Acad Orthop Surg. 2003;11(2):109–19.

    PubMed  Google Scholar 

  57. Goldhahn J, Féron J-M, Kanis J, Papapoulos S, Reginster J-Y, Rizzoli R, et al. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int. 2012;90(5):343–53.

    Article  CAS  PubMed  Google Scholar 

  58. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65.

    Article  CAS  PubMed  Google Scholar 

  59. Neogi T, Zhang Y. Epidemiology of osteoarthritis. Rheum Dis Clin N Am. 2013;39(1):1–19.

    Article  Google Scholar 

  60. Vahle JL, Long GG, Sandusky G, Westmore M, Ma YL, Sato M. Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol Pathol. 2004;32(4):426–38.

    Article  CAS  PubMed  Google Scholar 

  61. Cipriani C, Capriani C, Irani D, Bilezikian JP. Safety of osteoanabolic therapy: a decade of experience. J Bone Miner Res Off J Am Soc Bone Miner Res. 2012;27(12):2419–28.

    Article  Google Scholar 

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Conflict of interest

M. Sharifi and L. Ereifej have nothing to disclose.

E.M. Lewiecki has received institutional grant/research support from Amgen, Merck, and Eli Lilly; he has served on scientific advisory boards for Amgen, Merck, Eli Lilly, Radius Health, AgNovos Healthcare, Alexion, and NPS.

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  1. University of New Mexico School of Medicine, Albuquerque, NM, USA

    Maryam Sharifi, Lisa Ereifej & E. Michael Lewiecki

  2. New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA

    E. Michael Lewiecki

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  1. Maryam Sharifi
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Correspondence to E. Michael Lewiecki.

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Sharifi, M., Ereifej, L. & Lewiecki, E.M. Sclerostin and skeletal health. Rev Endocr Metab Disord 16, 149–156 (2015). https://doi.org/10.1007/s11154-015-9311-6

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