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Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)
Open accessAbstract
Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.
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“Inactivating mutations of this gene can produce the high-bone-mass disorder Van Buchem disease or sclerosteosis”
From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [73]
Experimental — accuracy not yet measuredIn the citing paper
“Mutations in genes that have highly enriched expression in osteocytes cause rare bone and mineral disorders.”
From Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease (2021) · cites this paper as [18]
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“Loss‐of‐function mutations in SOST are associated with an autosomal‐recessive disorder, sclerosteosis, which is characterized by progressive bone thickening.((3,4)) Individuals with Van Buchemdisease, a recessively inherited high bonemass disorder, have a deletion downstream of the SOST gene resulting in reduced expre…”
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“Mutations of the SOST gene have been identified as causative in sclerosteosis, a high bone mass disease in humans.((3,4)) A 52‐kb deletion of a regulatory region approximately 35 kb distal to the SOST gene is causative of the high bone mass phenotype seen in Van Buchem’s disease.”
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The Binding Between Sclerostin and LRP5 is Altered by DKK1 and by High-Bone Mass LRP5 Mutations
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BackgroundCortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease
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“…proteins that participate in Wnt signaling have also been implicated in postnatal bone formation, including the extracellular Wnt antagonist sclerostin (Balemans et al., 2001; Balemans et al., 2002; Brunkow et al., 2001; Li et al., 2008; Semenov et al., 2005), and Wnt10b (Bennett et al., 2005).”
BackgroundRole of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders
Marini, F., Giusti, F., Palmini, G., & Brandi, M. L. (2022) · Osteoporosis International · doi:10.1007/s00198-022-06523-7 · Cited by 154
“Two autosomal recessive high bone mass disorders, caused respectively by biallelic inactivating mutations of the SOST gene [61, 62] and by a 52-kb deletion of the SOST enhancer element, have been identified in humans, i.”
BackgroundMolecular-pathogenetic classification of genetic disorders of the skeleton
Superti‐Furga, A., Bonafé, L., & Rimoin, D. L. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.10233 · Cited by 146
WNT7B Promotes Bone Formation in part through mTORC1
Chen, J., Tu, X., Esen, E., Joeng, K. S., Lin, C., Arbeit, J. M., Rüegg, M. A., Hall, M. N., Ma, L., & Long, F. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004145 · Cited by 141
“LRP5 rendering it refractory to the WNT inhibitors such as SOST or DKK1, results in high bone mass in patients [4,5,6,7,8,9].”
BackgroundSclerostin antibody treatment enhances metaphyseal bone healing in rats
Agholme, F., Li, X., Isaksson, H., Ke, H. Z., & Aspenberg, P. (2010) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.135 · Cited by 142
“Mutations of the SOST gene cause high bone mass in humans.((6,7)) Similarly, a high-bone-mass phenotype is replicated in SOST knockout mice.”
BackgroundSpinal Cord Injury-Induced Osteoporosis: Pathogenesis and Emerging Therapies
Battaglino, R. A., Lazzari, A. A., Garshick, E., & Morse, L. R. (2012) · Current Osteoporosis Reports · doi:10.1007/s11914-012-0117-0 · Cited by 147
Crockett, J. C., Mellis, D. J., Scott, D. I., & Helfrich, M. H. (2011) · Osteoporosis International · doi:10.1007/s00198-010-1272-8 · Cited by 143
“This distinguishes the condition from other high bone mass disorders, such as sclerosteosis or van Buchem disease, which are caused by osteoblast overactivity and are characterised by the absence of fractures, even after trauma [15–17].”
BackgroundSclerostin in Mineralized Matrices and van Buchem Disease
van Bezooijen, R. L., Bronckers, A. L. J. J., Gortzak, R. A. T., Hogendoorn, P. C. W., van der Wee-Pals, L. J. A., Balemans, W., Oostenbroek, H. J., Hul, W. V., Hamersma, H. A., Dikkers, F. G., et al. (2009) · Journal of Dental Research · doi:10.1177/0022034509338340 · Cited by 138
“…generalized osteo sclerosis due to increased osteoblastic activity without any evidence of hor monal abnormalities (van Buchem et al., 1955; Truswell, 1958; Epstein et al., 1979; Balemans et al., 2001, 2002; Brunkow et al., 2001; StaehlingHampton et al., 2002; and our own unpublished observations).”
BackgroundSelf-citationThe Wnt signaling pathway and bone metabolism
Johnson, M. L., & Kamel, M. A. (2007) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e32816e06f9 · Cited by 140
Lee, C. A., & Einhorn, T. A. (2001) · Elsevier eBooks · doi:10.1016/b978-012470862-4/50002-7 · Cited by 135
DNA methylation contributes to the regulation of sclerostin expression in human osteocytes
Delgado‐Calle, J., Sañudo, C., Bolado‐Carrancio, A., Fernández, A. F., Arozamena, J., Pascual-Carra, M. A., Rodríguez-Rey, J. C., Fraga, M. F., Bonewald, L. F., & Riancho, J. A. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1491 · Cited by 134
“In fact, functional mutations of the SOST gene cause abnormal skeletal phenotypes in humans, characterized by high bone mineral density.((9,10))”
BackgroundProtective alleles and modifier variants in human health and disease
Harper, A. R., Nayee, S., & Topol, E. J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg4017 · Cited by 134
Sato, A. Y., Cregor, M. D., Delgado‐Calle, J., Condon, K. W., Allen, M. R., Peacock, M., Plotkin, L. I., & Bellido, T. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2869 · Cited by 135
Uitterlinden, A. G., Arp, P., Paeper, B. W., Charmley, P., Proll, S. C., Rivadeneira, F., Fang, Y., van Meurs, J. B. J., Britschgi, T. B., Latham, J. A., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/426458 · Cited by 132
“The gene that encodes sclerostin, or SOST, is mutated in the disorder sclerosteosis (SCL [MIM 269500]), which is characterized by massive, progressive bone overgrowth throughout life (Hansen 1967; Beighton 1988; Balemans et al. 2001; Brunkow et al. 2001).”
BackgroundInfluentialYoulten, S. E., Kemp, J. P., Logan, J. G., Ghirardello, E. J., Sergio, C. M., Dack, M. R. G., Guilfoyle, S. E., Leitch, V. D., Butterfield, N. C., Komla-Ebri, D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22517-1 · Cited by 133
van Lierop, A. H., Hamdy, N. A. T., Hamersma, H. A., van Bezooijen, R. L., Power, J., Loveridge, N., & Papapoulos, S. E. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.474 · Cited by 133
Sclerostin expression and functions beyond the osteocyte
Weivoda, M. M., Youssef, S. J., & Oursler, M. J. (2016) · Bone · doi:10.1016/j.bone.2016.11.024 · Cited by 133
“, Sclerostin expression and fu tissues, including cartilage, kidney, heart, and liver [1,2,15].”
BackgroundMaupin, K. A., Droscha, C. J., & Williams, B. O. (2013) · Bone Research · doi:10.4248/br201301004 · Cited by 133
Molecular Bases of the Regulation of Bone Remodeling by the Canonical Wnt Signaling Pathway
Glass, D. A., & Karsenty, G. (2006) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(05)73002-7 · Cited by 138
Targeted deletion of Sost distal enhancer increases bone formation and bone mass
Collette, N. M., Genetos, D. C., Economides, A. N., Xie, L., Shahnazari, M., Yao, W., Lane, N. E., Harland, R. M., & Loots, G. G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1207188109 · Cited by 139
Impact of Inflammation on the Osteoblast in Rheumatic Diseases
Baum, R., & Gravallese, E. M. (2013) · Current Osteoporosis Reports · doi:10.1007/s11914-013-0183-y · Cited by 137
Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis
Malluche, H. H., Davenport, D. L., Cantor, T. L., & Monier‐Faugere, M. (2014) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.09470913 · Cited by 131
β-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice
Chen, J., & Long, F. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1834 · Cited by 132
“Moreover, deficiency in either expression or function of sclerostin (SOST), a secreted protein that inhibits the binding of WNT molecules to LRP5/6, results in Van Buchem disease or sclerosteosis, both exhibiting high bone mass.((14,15)) Mouse ORIGINAL ARTICLE JBMR”
BackgroundMyeloma cells suppress osteoblasts through sclerostin secretion
Colucci, S. C., Brunetti, G., Oranger, A., Mori, G., Sardone, F., Specchia, G., Rinaldi, E., Curci, P., Liso, V., Passeri, G., et al. (2011) · Blood Cancer Journal · doi:10.1038/bcj.2011.22 · Cited by 130
Johnson, M. L., & Rajamannan, N. M. (2006) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-006-9003-3 · Cited by 134
“SOST mutations, for example, have been shown to results in the high bone mass phenotype, sclerosteosis [98, 99 ].”
BackgroundThe osteocyte plays multiple roles in bone remodeling and mineral homeostasis
Chen, H., Senda, T., & Kubo, K. (2015) · Medical Molecular Morphology · doi:10.1007/s00795-015-0099-y · Cited by 139
New developments in osteoarthritis and cartilage biology
Poulet, B., & Staines, K. A. (2016) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2016.02.009 · Cited by 128
“knockout mouse [37–39].”
Wnt signaling and the regulation of bone mass
Baron, R., & Rawadi, G. (2007) · Current Osteoporosis Reports · doi:10.1007/s11914-007-0006-0 · Cited by 127
“Genetic analysis demonstrated that sclerosteosis results from loss of function of the Sost gene product [55, 56 ], whereas van Buchem’s syndrome is associated with downregulation of the expression of the Sost gene due to a partial deletion of the regulatory region downstream of Sost [11,12].”
BackgroundJann, J., Gascon, S., Roux, S., & Faucheux, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207597 · Cited by 133
“Furthermore, the patients suffering from sclerosteosis and van Buchem disease (also known as hyperostosis corticalis generalisata), characterized by high bone mass, present a loss of the SOST gene function and SOST deletion on chromosome 17q (17q12–21 deletion), respectively [93,94].”
BackgroundIntercellular Cross-Talk Among Bone Cells: New Factors and Pathways
Sims, N. A., & Walsh, N. C. (2012) · Current Osteoporosis Reports · doi:10.1007/s11914-012-0096-1 · Cited by 128
Pοlyzos, S. A., Anastasilakis, A. D., Bratengeier, C., Woloszczuk, W., Παπαθεοδώρου, Α., & Terpos, E. (2011) · Osteoporosis International · doi:10.1007/s00198-010-1525-6 · Cited by 126
WNT signaling in bone development and homeostasis
Zhong, Z. A., Ethen, N. J., & Williams, B. O. (2014) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.159 · Cited by 129
Ardawi, M. M., Rouzi, A. A., & Qari, M. H. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3361 · Cited by 127
Metadata
- Authors
- Balemans, W.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Balemans, W.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-03-01
- Volume
- 10
- Issue
- 5
- Pages
- 537-543
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2119934014
- Cited by
- 1,147
- References
- 36
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 34 · 2023: 33 · 2022: 41 · 2021: 64 · 2020: 60 · 2019: 49 · 2018: 48 · 2017: 70 · 2016: 71 · 2015: 74 · 2014: 72 · 2013: 83 · 2012: 68
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Universiteit Antwerpen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- sclerosteosis, SOST gene, sclerostin, bone mineral density, bone formation regulation, van Buchem disease, positional cloning, nonsense mutation, splice site mutation, loss-of-function mutations, osteoporosis treatment, consanguineous family
- MeSH terms
- Amino Acid Sequence, Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 17, DNA Mutational Analysis, Genetic Markers, Humans, Genetic Linkage, Molecular Sequence Data, Osteochondrodysplasias, Protein Conformation, Proteins, RNA, Messenger, Bone Density, Sequence Homology, Amino Acid, DNA, Complementary, Bone Morphogenetic Proteins, Adaptor Proteins, Signal Transducing
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