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Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST. Sclerosteosis shares remarkable similarities with “high bone mass” diseases caused by “gain-of-function” mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins. We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. Our findings suggest that SOST is an antagonist for Wnt signaling and that the loss of SOST function likely leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients. Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST. Sclerosteosis shares remarkable similarities with “high bone mass” diseases caused by “gain-of-function” mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins. We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. Our findings suggest that SOST is an antagonist for Wnt signaling and that the loss of SOST function likely leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients. Sclerosteosis (1Beighton P. Durr L. Hamersma H. Ann. Intern. Med. 1976; 84: 393-397Crossref PubMed Scopus (100) Google Scholar) and Van Buchem (2van Buchem F.S.P. Hadders H.N. Ubbens R. Acta Radiol. (Stockh.). 1955; 44: 109-120Crossref PubMed Scopus (102) Google Scholar) disease are rare forms of autosomal recessive severe craniotubular hyperostoses. Both diseases are characterized by generalized overgrowth of bone tissue mostly manifested in cranial bones and in the diaphysis of tubular bones (3Hamersma H. Gardner J. Beighton P. Clin. Genet. 2003; 63: 192-197Crossref PubMed Scopus (174) Google Scholar). Bone overgrowth appears as early as at the age of 5 years and becoming more prominent with time. Sclerosteosis is linked to a loss of function of the SOST gene product (4Balemans W. Ebeling M. Patel N. Van Hul E. Olson P. Dioszegi M. Lacza C. Wuyts W. Van Den Ende J. Willems P. Paes-Alves A.F. Hill S. Bueno M. Ramos F.J. Tacconi P. Dikkers F.G. Stratakis C. Lindpaintner K. Vickery B. Foernzler D. Van Hul W. Hum. Mol. Genet. 2001; 10: 537-543Crossref PubMed Scopus (924) Google Scholar, 5Brunkow M.E. Gardner J.C. Van Ness J. Paeper B.W. Kovacevich B.R. Proll S. Skonier J.E. Zhao L. Sabo P.J. Fu Y. Alisch R.S. Gillett L. Colbert T. Tacconi P. Galas D. Hamersma H. Beighton P. Mulligan J. Am. J. Hum. Genet. 2001; 68: 577-589Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar), whereas Van Buchem disease is linked to a 52-kb deletion downstream of the SOST gene that causes down-regulation of SOST gene expression (6Balemans W. Patel N. Ebeling M. Van Hul E. Wuyts W. Lacza C. Dioszegi M. Dikkers F.G. Hildering P. Willems P.J. Verheij J.B. Lindpaintner K. Vickery B. Foernzler D. Van Hul W. J. Med. Genet. 2002; 39: 91-97Crossref PubMed Scopus (582) Google Scholar, 7Staehling-Hampton K. Proll S. Paeper B.W. Zhao L. Charmley P. Brown A. Gardner J.C. Galas D. Schatzman R.C. Beighton P. Papapoulos S. Hamersma H. Brunkow M.E. Am. J. Med. Genet. 2002; 110: 144-152Crossref PubMed Scopus (248) Google Scholar). The SOST gene encodes a secreted protein. During embryogenesis SOST expression is first detected in the mesenchyme at the sites of osteogenesis (8Kusu N. Laurikkala J. Imanishi M. Usui H. Konishi M. Miyake A. Thesleff I. Itoh N. J. Biol. Chem. 2003; 278: 24113-24117Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 9Winkler D.G. Sutherland M.K. Geoghegan J.C. Yu C. Hayes T. Skonier J.E. Shpektor D. Jonas M. Kovacevich B.R. Staehling-Hampton K. Appleby M. Brunkow M.E. Latham J.A. EMBO J. 2003; 22: 6267-6276Crossref PubMed Scopus (876) Google Scholar), and SOST expression is confined specifically to osteoblasts and osteocytes postnatally (9Winkler D.G. Sutherland M.K. Geoghegan J.C. Yu C. Hayes T. Skonier J.E. Shpektor D. Jonas M. Kovacevich B.R. Staehling-Hampton K. Appleby M. Brunkow M.E. Latham J.A. EMBO J. 2003; 22: 6267-6276Crossref PubMed Scopus (876) Google Scholar, 10van Bezooijen R.L. Roelen B.A. Visser A. van der Wee-Pals L. de Wilt E. Karperien M. Hamersma H. Papapoulos S.E. ten Dijke P. Lowik C.W. J. Exp. Med. 2004; 199: 805-814Crossref PubMed Scopus (693) Google Scholar). The increased rate of bone formation and elevated levels of serum alkaline phosphatase and osteocalcin in SOST mutation carriers suggest that excessive bone accumulation is most likely due to an increase in osteoblast activity upon the loss or decrease of SOST expression (5Brunkow M.E. Gardner J.C. Van Ness J. Paeper B.W. Kovacevich B.R. Proll S. Skonier J.E. Zhao L. Sabo P.J. Fu Y. Alisch R.S. Gillett L. Colbert T. Tacconi P. Galas D. Hamersma H. Beighton P. Mulligan J. Am. J. Hum. Genet. 2001; 68: 577-589Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar, 11Wergedal J.E. Veskovic K. Hellan M. Nyght C. Balemans W. Libanati C. Vanhoenacker F.M. Tan J. Baylink D.J. Van Hul W. J. Clin. Endocrinol. Metab. 2003; 88: 5778-5783Crossref PubMed Scopus (77) Google Scholar). Some studies suggest that the ability of SOST to decrease osteogenic activity of osteoblasts may be explained by its anti-BMP 1The abbreviations used are: BMP, bone morphogenetic protein; CM, conditioned medium; DKK, Dickkopf; Fz, Frizzled; HBM, high bone mass; LRP, low-density lipoprotein receptor-related protein; Xnr3, Xenopus nodal-related 3. activity (8Kusu N. Laurikkala J. Imanishi M. Usui H. Konishi M. Miyake A. Thesleff I. Itoh N. J. Biol. Chem. 2003; 278: 24113-24117Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 9Winkler D.G. Sutherland M.K. Geoghegan J.C. Yu C. Hayes T. Skonier J.E. Shpektor D. Jonas M. Kovacevich B.R. Staehling-Hampton K. Appleby M. Brunkow M.E. Latham J.A. EMBO J. 2003; 22: 6267-6276Crossref PubMed Scopus (876) Google Scholar, 10van Bezooijen R.L. Roelen B.A. Visser A. van der Wee-Pals L. de Wilt E. Karperien M. Hamersma H. Papapoulos S.E. ten Dijke P. Lowik C.W. J. Exp. Med. 2004; 199: 805-814Crossref PubMed Scopus (693) Google Scholar). However, SOST clearly has additional activities. SOST induces apoptosis of human osteoblastic cells, an activity that other BMP antagonists such as Noggin, Chordin, and Gremlin do not possess (12Sutherland M.K. Geoghegan J.C. Yu C. Turcott E. Skonier J.E. Winkler D.G. Latham J.A. Bone. 2004; 35: 828-835Crossref PubMed Scopus (188) Google Scholar). Furthermore, despite the ability of SOST to antagonize osteoblast differentiation induced by BMP, SOST does not inhibit BMP-induced SMAD protein phosphorylation or luciferase reporters driven by BMP-responsive elements (10van Bezooijen R.L. Roelen B.A. Visser A. van der Wee-Pals L. de Wilt E. Karperien M. Hamersma H. Papapoulos S.E. ten Dijke P. Lowik C.W. J. Exp. Med. 2004; 199: 805-814Crossref PubMed Scopus (693) Google Scholar). These data suggest that SOST may affect other signaling pathways that complement or mediate the effect of BMP on osteoblasts. Sclerosteosis and Van Buchem disease share a remarkable similarity with the “high bone mass” (HBM) phenotype, as these diseases are all caused by an increase of osteogenic activity of osteoblasts and osteocytes and are classified as “craniotubular hyperostoses” (13Johnson M.L. Harnish K. Nusse R. Van Hul W. J. Bone Miner. Res. 2004; 19: 1749-1757Crossref PubMed Scopus (183) Google Scholar). HBM is associated with “activating” mutations in the LRP5 gene (14Boyden L.M. Mao J. Belsky J. Mitzner L. Farhi A. Mitnick M.A. Wu D. Insogna K. Lifton R.P. N. Engl. J. Med. 2002; 346: 1513-1521Crossref PubMed Scopus (1345) Google Scholar, 15Little R.D. Carulli J.P. Del Mastro R.G. Dupuis J. Osborne M. Folz C. Manning S.P. Swain P.M. Zhao S.C. Eustace B. Lappe M.M. Spitzer L. Zweier S. Braunschweiger K. Benchekroun Y. Hu X. Adair R. Chee L. FitzGerald M.G. Tulig C. Caruso A. Tzellas N. Bawa A. Franklin B. McGuire S. Nogues X. Gong G. Allen K.M. Anisowicz A. Morales A.J. Lomedico P.T. Recker S.M. 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Thus, a lack of SOST function exhibits phenotypes related to excessive LRP5 function, implying the possibility that SOST may antagonize LRP5 function. Interestingly, SOST is related to WISE, a secreted protein that binds to the Wnt coreceptor LRP6 and modulates (activates or inhibits) Wnt signaling in a cell context-dependent manner (20Itasaki N. Jones C.M. Mercurio S. Rowe A. Domingos P.M. Smith J.C. Krumlauf R. Development. 2003; 130: 4295-4305Crossref PubMed Scopus (273) Google Scholar). Here we show that SOST binds to both LRP5 and LRP6 and inhibits the canonical Wnt pathway. Our results suggest that sclerosteosis and Van Buchem disease may be a result of hyperactive Wnt signaling. SOST cDNA was cloned by PCR using IMAGE cDNA clone 2380708 as the template. SOST/pcDNA3.1+ contains the full-length SOST. SOST-Myc/pcDNA3 and SOST-IgG/pcDNA3.1+ were generated by fusion at the 5′-end of full-length SOST cDNA without the stop codon with the 6× Myc epitope tag from CS2+MT or the IgG tag from IgG/pRK5 (21Hsieh J.C. Rattner A. Smallwood P.M. Nathans J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3546-3551Crossref PubMed Scopus (292) Google Scholar). Kremen2/pCS (22Mao B. Wu W. Davidson G. Marhold J. Li M. Mechler B.M. Delius H. Hoppe D. Stannek P. Walter C. Glinka A. Niehrs C. Nature. 2002; 417: 664-667Crossref PubMed Scopus (873) Google Scholar), DKK1-FLAG/CS2+ (23Krupnik V.E. Sharp J.D. Jiang C. Robison K. Chickering T.W. Amaravadi L. Brown D.E. Guyot D. Mays G. Leiby K. Chang B. Duong T. Goodearl A.D. Gearing D.P. Sokol S.Y. McCarthy S.A. Gene. 1999; 238: 301-313Crossref PubMed Scopus (421) Google Scholar), LRP6N-Myc/pcDNA3, Xwnt8/CS2+ (19Tamai K. Semenov M. Kato Y. Spokony R. Liu C. Katsuyama Y. Hess F. Saint-Jeannet J.P. He X. 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Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). Xenopus and were as described (24Semenov M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). and cells were in high with conditioned was from were from were using the cells were were with of A. Curr. Biol. 2003; 13: Full Text Full Text PDF PubMed Scopus Google Scholar) and of with other as in the using were with were and for and luciferase luciferase were Xenopus a and to Wnt and Wnt R. J. Dev. 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Thus, SOST activity and does not anti-BMP activity in Xenopus the ability of SOST to inhibit Wnt signaling in mammalian cells, we the A. Curr. Biol. 2003; 13: Full Text Full Text PDF PubMed Scopus Google Scholar, V. N. P.J. van D. de R. B. H. PubMed Scopus Google Scholar), which is driven by cell elements and is to Wnt signaling. The was in cells with a of a SOST expression Wnt signaling in a manner the SOST protein we generated from cells with the We that the of the SOST protein The SOST associated with cells and in the an of as with the of SOST with from to and from to were detected in the These may be to SOST has sites for at and and for at K. A. R. S. PubMed Scopus Google Scholar). We SOST for of Wnt signaling. SOST accumulation induced by in cells Thus, secreted SOST antagonizes activity sclerosteosis with the loss of SOST and HBM disease linked to hyperactive LRP5 signaling suggest that SOST may antagonize Wnt signaling binding to the binding SOST and LRP5 as as we a fusion which SOST with the of and the extracellular of LRP5 and LRP6 with the Myc epitope and We that SOST with LRP5 and LRP6 not with a low-density lipoprotein Furthermore, was in with and SOST specifically to LRP5 and LRP6 an additional for the binding we used which has a to that of in the CM, Fz8CRD-IgG was to of LRP5 or LRP6 protein and we SOST inhibit LRP5 or LRP6 signaling activities. LRP5 and LRP6 of Wnt signaling in the LRP5 or LRP6 with SOST signaling by LRP5 or LRP6 that SOST antagonizes signaling by LRP5 and of LRP5 or LRP6 and in the of Wnt has been to be an in Wnt signaling (19Tamai K. Semenov M. Kato Y. Spokony R. Liu C. Katsuyama Y. Hess F. Saint-Jeannet J.P. He X. Nature. 2000; 407: 530-535Crossref PubMed Scopus (1103) Google Scholar). we (19Tamai K. Semenov M. Kato Y. Spokony R. Liu C. Katsuyama Y. Hess F. Saint-Jeannet J.P. He X. Nature. 2000; 407: 530-535Crossref PubMed Scopus (1103) Google Scholar), Fz8CRD-IgG with the extracellular domain of LRP6 and the of induced the formation of and LRP6 The of or SOST such complex formation. alkaline used as a effect on complex formation Thus, SOST appears to be to Wnt-induced complex formation. We have that Wnt with LRP5 and LRP6 and Wnt-induced complex formation and (24Semenov M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). The activity of be by which (22Mao B. Wu W. Davidson G. Marhold J. Li M. Mechler B.M. Delius H. Hoppe D. Stannek P. Walter C. Glinka A. Niehrs C. Nature. 2002; 417: 664-667Crossref PubMed Scopus (873) Google Scholar). We the and SOST or in Wnt signaling We Wnt signaling by LRP5 in cells and used a of SOST or that of Wnt effect of Wnt signaling activity by in cells LRP5 with was likely due to gene by Wnt Schwartz A. EMBO J. PubMed Scopus Google Scholar). in Wnt signaling SOST and not in Wnt signaling Thus, SOST does not with in Wnt signaling we that the product of the gene in sclerosteosis and Van Buchem is an for the Wnt coreceptors LRP5 and LRP6 and an of the canonical signaling in both mammalian cells and Xenopus These findings not the of secreted that to the Wnt coreceptors LRP5 and LRP6 have for of Van Buchem and bone diseases associated with LRP5 mutations such as HBM and has that the signaling by LRP5 and LRP6 a in mammalian bone (13Johnson M.L. Harnish K. Nusse R. Van Hul W. J. Bone Miner. Res. 2004; 19: 1749-1757Crossref PubMed Scopus (183) Google Scholar). mutations of LRP5 are associated with the recessive Y. N. G. S. H. T. D. M. K. J. W. S. G. S. J. M. J.A. Beighton P. R.G. L.M. C. B. De A. B. M.L. B. R.C. T. A. H. K. A. D. M. E. T. L. R.S. M. H. E. B. B. A. W. van Van Hul W. M. M. B. T. R. B.R. Warman M.L. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), whereas “gain-of-function” mutations of LRP5 are associated with HBM diseases (14Boyden L.M. Mao J. Belsky J. Mitzner L. Farhi A. Mitnick M.A. Wu D. Insogna K. Lifton R.P. N. Engl. J. Med. 2002; 346: 1513-1521Crossref PubMed Scopus (1345) Google Scholar, 15Little R.D. Carulli J.P. Del Mastro R.G. Dupuis J. Osborne M. Folz C. Manning S.P. Swain P.M. Zhao S.C. Eustace B. Lappe M.M. Spitzer L. Zweier S. Braunschweiger K. Benchekroun Y. Hu X. Adair R. Chee L. FitzGerald M.G. Tulig C. Caruso A. Tzellas N. Bawa A. Franklin B. McGuire S. Nogues X. Gong G. Allen K.M. Anisowicz A. Morales A.J. Lomedico P.T. Recker S.M. Van Eerdewegh P. Recker R.R. Johnson M.L. Am. J. Hum. Genet. 2002; 70: 11-19Abstract Full Text Full Text PDF PubMed Scopus (1096) Google Scholar). all LRP5 mutations from HBM are in the first of the LRP5 extracellular domain Wesenbeeck L. Cleiren E. Gram J. Beals R.K. Benichou O. Scopelliti D. Key L. Renton T. Bartels C. Gong Y. Warman M.L. De Vernejoul M.C. Bollerslev J. Van Hul W. Am. J. Hum. Genet. 2003; 72: 763-771Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar). The by which these mutations the increase of signaling bone LRP5 to of LRP5 by was to for increased LRP5 signaling (14Boyden L.M. Mao J. Belsky J. Mitzner L. Farhi A. Mitnick M.A. Wu D. Insogna K. Lifton R.P. N. Engl. J. Med. 2002; 346: 1513-1521Crossref PubMed Scopus (1345) Google Scholar, Y. Y. Li X. Zhang J. Mao J. Li Z. J. Li L. S. Wu D. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). SOST is in osteoblasts and and a loss or down-regulation of SOST function in sclerosteosis and Van Buchem disease exhibits increased bone SOST appears to be an of bone likely the of LRP5 and LRP6 function. be to LRP5 mutations associated with HBM disease result in SOST of LRP5 function. SOST shares with WISE, which was to LRP6 and to or inhibit Wnt signaling in a context-dependent manner (20Itasaki N. Jones C.M. Mercurio S. Rowe A. Domingos P.M. Smith J.C. Krumlauf R. Development. 2003; 130: 4295-4305Crossref PubMed Scopus (273) Google Scholar). These related share the domain that the of proteins. SOST and is that whereas SOST as an antagonist for signaling in mammalian cells and Xenopus function as a that signaling to a (20Itasaki N. Jones C.M. Mercurio S. Rowe A. Domingos P.M. Smith J.C. Krumlauf R. Development. 2003; 130: 4295-4305Crossref PubMed Scopus (273) Google Scholar). The and function of Wnt activity of is of to SOST with the antagonist A. Wu W. Delius H. A.P. C. Niehrs C. Nature. 1998; PubMed Scopus Google Scholar), which does not show similarity with SOST. (24Semenov M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar), SOST has the ability to complex formation in an in a for the SOST However, SOST of Wnt signaling is to the of a protein that binds to (22Mao B. Wu W. Davidson G. Marhold J. Li M. Mechler B.M. Delius H. Hoppe D. Stannek P. Walter C. Glinka A. Niehrs C. Nature. 2002; 417: 664-667Crossref PubMed Scopus (873) Google Scholar). Thus, both are the of and SOST be by other Some studies suggest that SOST and BMP and as BMP antagonists (8Kusu N. Laurikkala J. Imanishi M. Usui H. Konishi M. Miyake A. Thesleff I. Itoh N. J. Biol. Chem. 2003; 278: 24113-24117Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 9Winkler D.G. Sutherland M.K. Geoghegan J.C. Yu C. Hayes T. Skonier J.E. Shpektor D. Jonas M. Kovacevich B.R. Staehling-Hampton K. Appleby M. Brunkow M.E. Latham J.A. EMBO J. 2003; 22: 6267-6276Crossref PubMed Scopus (876) Google Scholar, 10van Bezooijen R.L. Roelen B.A. Visser A. van der Wee-Pals L. de Wilt E. Karperien M. Hamersma H. Papapoulos S.E. ten Dijke P. Lowik C.W. J. Exp. Med. 2004; 199: 805-814Crossref PubMed Scopus (693) Google Scholar, W. J. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. L. Thesleff I. Itoh N. Dev. Biol. 2003; PubMed Scopus (210) Google Scholar). However, in Xenopus SOST exhibits antagonist BMP, both affect Wnt signaling. whereas BMP antagonists such as and tissue and formation of BMP SOST and to do were at high levels (20Itasaki N. Jones C.M. Mercurio S. Rowe A. Domingos P.M. Smith J.C. Krumlauf R. Development. 2003; 130: 4295-4305Crossref PubMed Scopus (273) Google Scholar). Thus, SOST and may at have BMP antagonist activities. with the binding of SOST and for are of and (8Kusu N. Laurikkala J. Imanishi M. Usui H. Konishi M. Miyake A. Thesleff I. Itoh N. J. Biol. Chem. 2003; 278: 24113-24117Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, J. Y. L. Thesleff I. Itoh N. Dev. Biol. 2003; PubMed Scopus (210) Google Scholar). studies be to SOST and function as antagonists or function as antagonists for both Wnt and BMP signaling. the bone phenotypes of loss of SOST function and LRP5 SOST and LRP5 may be a for the of bone diseases such as We of the He for and
Semenov et al. (Sat,) studied this question.
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