Sclerostin: Current Knowledge and Future Perspectives

National Osteoporosis Foundation (2008) Facts on osteoporosis. http://www.nof.org/osteoporosis/diseasefacts.htm

van Buchem FS, Hadders HN, Ubbens R (1955) An uncommon familial systemic disease of the skeleton: hyperostosis corticalis generalisata familiaris. Acta Radiol 44:109–120

Hamersma H, Gardner J, Beighton P (2003) The natural history of sclerosteosis. Clin Genet 63:192–197

Beighton P, Barnard A, Hamersma H, van der Wouden A (1984) The syndromic status of sclerosteosis and van Buchem disease. Clin Genet 25:175–181

Beighton P (1988) Sclerosteosis. J Med Genet 25:200–203

Gardner JC, van Bezooijen RL, Mervis B, Hamdy NAT, Löwik CWGM, Hamersma H, Beighton P, Papapoulos SE (2005) Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab 90:6392–6395

van Bezooijen RL, ten Dijke P, Papapoulos SE, Löwik CWGM (2005) SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 16:319–327

van Bezooijen RL, Papapoulos SE, Hamdy NAT, Lowik CWGM (2008) SOST/sclerostin; an osteocyte-derived inhibitor of bone formation that antagonizes canonical Wnt signaling. In: Raisz LG, Martin TJ, Bilezikian JP (eds) Principles of bone biology. Academic Press, New York, pp 139–152

Hill SC, Stein SA, Dwyer A, Altman J, Dorwart R, Doppman J (1986) Cranial CT findings in sclerosteosis. AJNR Am J Neuroradiol 7:505–511

Stein SA, Witkop C, Hill SC, Fallon MD, Viernstein L, Gucer G, McKeever P, Long D, Altman J, Miller NR, Teitelbaum SL, Schlesinger S (1983) Sclerosteosis: neurogenetic and pathophysiologic analysis of an American kinship. Neurology 33:267–277

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 CWGM (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814

van Bezooijen RL, Bronckers AL, Gortzak RA, Hogendoorn PC, van der Wee-Pals L, Balemans W, Oostenbroek HJ, van Hul W, Hamersma H, Dikkers FG, Hamdy NAT, Papapoulos SE, Löwik CWGM (2009) Sclerostin in mineralized matrices and van Buchem disease. J Dent Res 88:569–574

Epstein S, Hamersma H, Beighton P (1979) Endocrine function in sclerosteosis. S Afr Med J 55:1105–1110

Beighton P, Durr L, Hamersma H (1976) The clinical features of sclerosteosis. A review of the manifestations in twenty-five affected individuals. Ann Intern Med 84:393–397

Wergedal JE, Veskovic K, Hellan M, Nyght C, Balemans W, Libanati C, Vanhoenacker FM, Tan J, Baylink DJ, van Hul W (2003) 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 88:5778–5783

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 SC, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, 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). Hum Mol Genet 10:537–543

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 (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589

Balemans W, Cleiren E, Siebers U, Horst J, van Hul W (2005) A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 36:943–947

Kim CA, Honjo R, Bertola D, Albano L, Oliveira L, Jales S, Siqueira J, Castilho A, Balemans W, Piters E, Jennes K, van Hul W (2008) A known SOST gene mutation causes sclerosteosis in a familial and an isolated case from Brazilian origin. Genet Test 12:475–479

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 (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97

Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, Gardner JC, Galas D, Schatzman RC, Beighton P, Papapoulos SE, Hamersma H, Brunkow ME (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12–q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110:144–152

Loots GG, Kneissel M, Keller H, Baptist M, Chang J, Collette NM, Ovcharenko D, Plajzer-Frick I, Rubin EM (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in van Buchem disease. Genome Res 15:928–935

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 (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CWGM, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844

Ohyama Y, Nifuji A, Maeda Y, Amagasa T, Noda M (2004) Spaciotemporal association and bone morphogenetic protein regulation of sclerostin and osterix expression during embryonic osteogenesis. Endocrinology 145:4685–4692

Balemans W, van Hul W (2002) Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol 250:231–250

Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, Thesleff I, Itoh N (2003) Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem 278:24113–24117

Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, Manolagas SC, Jilka RL (2005) Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–4583

Pockwinse SM, Wilming LG, Conlon DM, Stein GS, Lian JB (1992) Expression of cell growth and bone specific genes at single cell resolution during development of bone tissue-like organization in primary osteoblast cultures. J Cell Biochem 49:310–323

Sutherland MK, Geoghegan JC, Yu C, Winkler DG, Latham JA (2004) Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Bone 35:448–454

Irie K, Ejiri S, Sakakura Y, Shibui T, Yajima T (2008) Matrix mineralization as a trigger for osteocyte maturation. J Histochem Cytochem 56:561–567

Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37:148–158

Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA (2004) Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone 35:828–835

Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869

Avsian-Kretchmer O, Hsueh AJ (2004) Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists. Mol Endocrinol 18:1–12

van Bezooijen RL, Papapoulos SE, Löwik CWGM (2005) Bone morphogenetic proteins and their antagonists: the sclerostin paradigm. J Endocrinol Invest 28:15–17

Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (2006) Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res 21:1738–1749

Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480

Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna KL, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521

Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, van Eerdewegh P, Recker RR, Johnson ML (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70:11–19

Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, de Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887

Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775

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 CWGM (2007) Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22:19–28

Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, Muzylak M, Greenslade K, Moore AR, Zhang L, Gong J, Qian X, Paszty C, Taylor RJ, Robinson MK, Carr MD (2009) Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem 284:10890–10900

Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (2009) NMR structure of the Wnt modulator protein Sclerostin. Biochem Biophys Res Commun 380:160–165

Hens JR, Wilson KM, Dann P, Chen X, Horowitz MC, Wysolmerski JJ (2005) TOPGAL mice show that the canonical Wnt signaling pathway is active during bone development and growth and is activated by mechanical loading in vitro. J Bone Miner Res 20:1103–1113

Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615

Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schutz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G (2008) Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135:825–837

Knothe Tate ML, Adamson JR, Tami AE, Bauer TW (2004) The osteocyte. Int J Biochem Cell Biol 36:1–8

Han Y, Cowin SC, Schaffler MB, Weinbaum S (2004) Mechanotransduction and strain amplification in osteocyte cell processes. Proc Natl Acad Sci USA 101:16689–16694

Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K (2007) Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 5:464–475

Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728

Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading via antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 24:1651–1661

Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH (2006) The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem 281:23698–23711

Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875

Moustafa A, Sugiyama T, Saxon LK, Zaman G, Sunters A, Armstrong VJ, Javaheri B, Lanyon LE, Price JS (2009) The mouse fibula as a suitable bone for the study of functional adaptation to mechanical loading. Bone 44:930–935

Pleiner-Duxneuner J, Zwettler E, Paschalis E, Roschger P, Nell-Duxneuner V, Klaushofer K (2009) Treatment of osteoporosis with parathyroid hormone and teriparatide. Calcif Tissue Int 84:159–170

Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, Keller H (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22:1957–1967

Silvestrini G, Ballanti P, Leopizzi M, Sebastiani M, Berni S, di Vito M, Bonucci E (2007) Effects of intermittent parathyroid hormone (PTH) administration on SOST mRNA and protein in rat bone. J Mol Histol 38:261–269

O’Brien CA, Plotkin LI, Galli C, Goellner JJ, Gortazar AR, Allen MR, Robling AG, Bouxsein M, Schipani E, Turner CH, Jilka RL, Weinstein RS, Manolagas SC, Bellido T (2008) Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS One 3:e2942

Kramer I, Loots GG, Studer A, Keller H, Kneissel M (2009) Parathyroid hormone (PTH) induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res 25:178–189

Sevetson B, Taylor S, Pan Y (2004) Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). J Biol Chem 279:13849–13858

Yao W, Cheng Z, Pham A, Busse C, Zimmermann EA, Ritchie RO, Lane NE (2008) Glucocorticoid-induced bone loss in mice can be reversed by the actions of parathyroid hormone and risedronate on different pathways for bone formation and mineralization. Arthritis Rheum 58:3485–3497

Kamiya N, Ye L, Kobayashi T, Mochida Y, Yamauchi M, Kronenberg HM, Feng JQ, Mishina Y (2008) BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development 135:3801–3811

Goldring SR, Goldring MB (2007) Eating bone or adding it: the Wnt pathway decides. Nat Med 13:133–134

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 (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588

Ominsky M, Stouch B, Doellgast G, Gong J, Cao J, Gao Y, Tipton B, Haldankar R, Winters A, Chen Q, Graham K, Zhou L, Hale M, Henry A, Lightwood D, Moore A, Popplewell A, Robinson M, Vlasseros F, Jolette J, Smith SY, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (2006) Administration of sclerostin monoclonal antibodies to female cynomolgus monkeys results in increased bone formation, bone mineral density and bone strength. Read at the Annual Meeting of the American Society for Bone and Mineral Research, 2006 Sept 18, Philadelphia, PA

Eddleston A, Marenzana M, Moore AR, Stephens P, Muzylak M, Marshall D, Robinson MK (2009) A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis. J Bone Miner Res 24:1662–1671

Padhi D, Stouch B, Jang G, Fang L, Darling M, Glise H, Robinson M, Harris SE, Posvar E (2007) Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women. J Bone Miner Res 21 Suppl 1:S37

Whyte MP, Reinus WH, Mumm S (2004) High-bone-mass disease and LRP5. N Engl J Med 350:2096–2099

Rickels MR, Zhang X, Mumm S, Whyte MP (2005) Oropharyngeal skeletal disease accompanying high bone mass and novel LRP5 mutation. J Bone Miner Res 20:878–885

Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, Dobrovic A, Slavin J, Choong PF, Simmons PJ, Dawid IB, Thomas DM (2009) Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest 119:837–851