Cited by 1,147Bone Metabolism and DiseasesDermatological and Skeletal DisordersBone health and osteoporosis research

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Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)

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Balemans, W.·2001·Human Molecular Genetics

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Abstract

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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Background
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Patel, M. A., Fraser, D. D., Daley, M., Cepinskas, G., Veraldi, N., & Grazioli, S. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00806-x · Cited by 11
Role of sclerostin deletion in bisphosphonate-induced osteonecrosis of the jaw
Nakashima, F., Matsuda, S., Ninomiya, Y., Ueda, T., Yasuda, K., Hatano, S., Shimada, S., Furutama, D., Memida, T., Kajiya, M., et al. (2024) · Bone · doi:10.1016/j.bone.2024.117200 · Cited by 10
Osteocyte Biology
Bonewald, L. F. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-415853-5.00010-8 · Cited by 14
A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study
Zhao, J., Xia, W., Nie, M., Zheng, X. S., Wang, Q., Wang, X., Wang, W., Ning, Z., Huang, W., Jiang, Y., et al. (2012) · Bone · doi:10.1016/j.bone.2012.01.003 · Cited by 10
“Many genes in which mutations result in rare bone diseases are also contributors to the variation in BMD in the general population, examples including SOST [21–23], LRP5 [24,25] and CLCLN7 [26,27].”
Background
Dkk1 KO Mice Treated with Sclerostin Antibody Have Additional Increases in Bone Volume
Morse, A., Cheng, T. L., Schindeler, A., McDonald, M. M., Mohanty, S. T., Kneissel, M., Krämer, I., & Little, D. G. (2018) · Calcified Tissue International · doi:10.1007/s00223-018-0420-6 · Cited by 10
Anatomical similarity between the Sost‐knockout mouse and sclerosteosis in humans
Schwarze, U. Y., Dobsak, T., Gruber, R., & Bookstein, F. L. (2019) · The Anatomical Record · doi:10.1002/ar.24318 · Cited by 10
Cardiovascular Safety of Anti-Sclerostin Therapy in Chronic Kidney Disease
Cejka, D. (2021) · Metabolites · doi:10.3390/metabo11110770 · Cited by 10
Novel therapeutic targets in myeloma bone disease
Webb, S. L., & Edwards, C. M. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12742 · Cited by 10
“Sclerostin, a well-characterized Wnt antagonist, is implicated in several bone-related pathological diseases such as sclerosteosis and van Buchem’s disease (Balemans et al., 2001; 2002) and now sclerostin in myeloma (Brunetti et al.”
Background
Sclerosteosis caused by a novel nonsense mutation of SOST in a consanguineous family
He, W., Chen, C., Pan, C., Zhang, M., Yu, X., Wang, D. W., & Hu, S. (2015) · Clinical Genetics · doi:10.1111/cge.12655 · Cited by 10
“Genetic refinement of the two diseases was mapped to chromosome 17q12-q21, which contains the responsible gene termed SOST (5, 6).”
Background
Expression of sclerostin in the developing zebrafish (Danio rerio) brain and skeleton
McNulty, M. S., Bedell, V. M., Greenwood, T. M., Craig, T. A., Ekker, S. C., & Kumar, R. (2012) · Gene Expression Patterns · doi:10.1016/j.gep.2012.04.003 · Cited by 10
“A loss or reduction in expression of the protein, results in the bone dysplasias, sclerosteosis or van Buchem disease (Balemans et al., 2001; Balemans et al., 2002; Brunkow et al., 2001).”
Influential
Sclerosteosis (craniotubular hyperostosis-syndactyly) with complex hyperphalangy of the index finger
Yagi, H., Takagi, M., Hasegawa, Y., Kayserili, H., & Nishimura, G. (2015) · Pediatric Radiology · doi:10.1007/s00247-015-3292-1 · Cited by 10
Sclerosing bone dysplasias with involvement of the craniofacial skeleton
Waterval, J. J., Borra, V., Hul, W. V., Stokroos, R. J., & Manni, J. J. (2013) · Bone · doi:10.1016/j.bone.2013.12.003 · Cited by 10
Modeling craniofacial and skeletal congenital birth defects to advance therapies
Neben, C. L., Roberts, R. R., Dipple, K. M., Merrill, A. E., & Klein, O. D. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw171 · Cited by 10
Estrogen Receptors Critically Regulate Bones’ Adaptive Responses to Loading
Lanyon, L. E., Armstrong, V. J., Saxon, L., Sunters, A., Sugiyama, T., Zaman, G., & Price, J. S. (2007) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-008-9011-9 · Cited by 10
“This may be the case in some genetic strains of mice [66, 67]; in high bone mass humans [68–72] and in regions of the skeleton, such as the skull, where (presumably due to genetic instructions) bone mass sufficient to provide adequate fracture resistance is achieved in the absence of significant functional loading.”
Background
Introduction on Psychopharmacogenetics
Gorwood, P. A. P. M., & FOOT, E. A. (2006) · Springer eBooks · doi:10.1007/0-387-34577-2_1 · Cited by 10
“2001) or osteoporosis (Balemans et al. 2001) have shown that high complexity of the disorder, presence of moderate heritability, or the existence of phenotypical heterogeneity, should not be considered as factors incompatible with the use of genetics.”
Background
Osteocytes
Bonewald, L. F. (2013) · Primer on the metabolic bone diseases and disorders of mineral metabolism · doi:10.1002/9781118453926.ch4 · Cited by 10
A Sclerostin Super-Producer Cell Line Derived from the Human Cell Line SaOS-2: A New Tool for the Study of the Molecular Mechanisms Driving Sclerostin Expression
Pérez-Campo, F. M., Sañudo, C., Delgado‐Calle, J., Arozamena, J., Zarrabeitia, M. T., & Riancho, J. A. (2014) · Calcified Tissue International · doi:10.1007/s00223-014-9880-5 · Cited by 9
“Although SOST mRNA is expressed in many tissues during embryogenesis (heart, liver and kidney) [6–8], its postnatal expression in adult human tissues is largely”
Background
Obesity and Bone Loss at Menopause: The Role of Sclerostin
Marzullo, P., Mele, C., Mai, S., Nardone, A., Scacchi, M., & Aimaretti, G. (2021) · Diagnostics · doi:10.3390/diagnostics11101914 · Cited by 9
“Importantly, Wnt is antagonized by the osteocyte-secreted product of the SOST gene, sclerostin [28,29].”
Background
Bone Material Properties in Bone Diseases Affecting Children
Raimann, A., Misof, B. M., Fratzl, P., & Fratzl‐Zelman, N. (2023) · Current Osteoporosis Reports · doi:10.1007/s11914-023-00822-6 · Cited by 9
“Ordered bone lamellar structure, abundant cuboidal active osteoblasts, osteoid of normal thickness but greatly increased indices of bone formation, whereas number of osteoclasts in the low-normal range were reported in bone specimens from children with sclerosteosis [201, 203, 204].”
Localization of the Gene for Hyperostosis Cranialis Interna to Chromosome 8p21 with Analysis of Three Candidate Genes
Borra, V., Waterval, J. J., Stokroos, R. J., Manni, J. J., & Hul, W. V. (2013) · Calcified Tissue International · doi:10.1007/s00223-013-9732-8 · Cited by 9
“SOST was identified by positional cloning studies in families with Van Buchem disease [7] and sclerosteosis [9].”
BackgroundInfluential
How rare bone diseases have informed our knowledge of complex diseases
Johnson, M. L. (2016) · BoneKEy Reports · doi:10.1038/bonekey.2016.69 · Cited by 9
Is there a role for newer biomarkers in chronic kidney disease‐mineral and bone disorder management?
Tan, S., & Cai, M. M. (2017) · Nephrology · doi:10.1111/nep.13015 · Cited by 9
“Sclerostin is the transcriptional product of the SOST gene.(46) The protein is mostly produced by osteocytes, the most abundant cell type in the bone.”
Background
The Microdamage and Expression of Sclerostin in Peri-implant Bone under One-time Shock Force Generated by Impact
Diao, X., Li, Z., An, B., Xin, H., Wu, Y., Li, K., Feng, F., & Dou, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-06867-9 · Cited by 9
Sost deficiency leads to reduced mechanical strains at the tibia midshaft in strain-matched in vivo loading experiments in mice
Albiol, L., Cilla, M., Pflanz, D., Krämer, I., Kneissel, M., Duda, G. N., Willie, B. M., & Checa, S. (2018) · Journal of The Royal Society Interface · doi:10.1098/rsif.2018.0012 · Cited by 9
Conditional deletion of E11/Podoplanin in bone protects against ovariectomy-induced increases in osteoclast formation and activity
Staines, K. A., Hopkinson, M., Dillon, S., Stephen, L. A., Fleming, R., Sophocleous, A., Buttle, D. J., Pitsillides, A. A., & Farquharson, C. (2020) · Bioscience Reports · doi:10.1042/bsr20190329 · Cited by 9
Pathophysiology of Osteoporosis
Raisz, L. G., Bilezikian, J. P., & Martin, T. J. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373884-4.00082-3 · Cited by 11
Circulating sclerostin is associated with bone mineral density independent of HIV-serostatus
Ross, R. D., Sharma, A., Shi, Q., Hoover, D. R., Weber, K. M., Tien, P. C., French, A. L., Al‐Harthi, L., & Yin, M. T. (2020) · Bone Reports · doi:10.1016/j.bonr.2020.100279 · Cited by 9
Role of Osteocytes in Cancer Progression in the Bone and the Associated Skeletal Disease
Adhikari, M., & Delgado‐Calle, J. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-021-00679-7 · Cited by 9
SOST/Sclerostin
van Bezooijen, R. L., Papapoulos, S. E., Hamdy, N. A. T., & Löwik, C. W. G. M. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373884-4.00014-8 · Cited by 9
Comparison of Serum Dkk1 (Dickkopf-1) and Bone Mineral Density in Patients on Bisphosphonate Treatment Vs no Treatment
Memon, A. R., Butler, J. S., O'Riordan, M. V., Guerin, E., Dimitrov, B. D., & Harty, J. A. (2012) · Journal of Clinical Densitometry · doi:10.1016/j.jocd.2012.07.003 · Cited by 9
“ders of increased bonemass, such as sclerosteosis, VanBuchem disease, osteopetrosis, and endosteal hyperostosis (11,16,17).”
Background
TIEG1-NULL OSTEOCYTES DISPLAY DEFECTS IN THEIR MORPHOLOGY, DENSITY AND SURROUNDING BONE MATRIX
Haddad, O., Hawse, J. R., Subramaniam, M., Spelsberg, T. C., & Bensamoun, S. F. (2009) · Journal of Musculoskeletal Research · doi:10.1142/s0218957709002304 · Cited by 9
Wnt Proteins in Mineralized Tissue Development and Homeostasis
Tompkins, K. A. (2011) · Connective Tissue Research · doi:10.3109/03008207.2011.616610 · Cited by 10
“Mutation of the Sost gene causes sclerosteosis, a condition in which there is pathological overgrowth of the bones of the skull among others, resulting in entrapment of the cranial nerves which can lead to a loss of vision or hearing [64,65].”
Background
Relevance of Wnt signaling for osteoanabolic therapy
Yorgan, T. A., & Schinke, T. (2014) · Molecular and Cellular Therapies · doi:10.1186/2052-8426-2-22 · Cited by 8
“One putative Wnt signaling antagonist, termed Sclerostin, was first identified by human genetics in individuals with increased bone formation, as discussed below [16,17].”
Background
Sclerostin: More than a bone formation brake
Rauch, F., & Adachi, R. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf4628 · Cited by 9
Engineered T Cell Therapies from a Drug Development Viewpoint
Chen, F., Fraietta, J. A., June, C. H., Xu, Z., Melenhorst, J. J., & Lacey, S. F. (2018) · Engineering · doi:10.1016/j.eng.2018.11.010 · Cited by 9
“The disease association of a drug target is revealed by naturally occurring mutations, which can be the case for some targets, such as sclerostin [57].”
Background
Osteocytes
Bonewald, L. F. (2008) · Elsevier eBooks · doi:10.1016/b978-012370544-0.50010-0 · Cited by 9
Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
Huybrechts, Y., Boudin, E., Hendrickx, G., Steenackers, E., Hamdy, N. A. T., Mortier, G. R., Diaz‐Guerra, G. M., Bracamonte, M. S., Appelman‐Dijkstra, N. M., & Hul, W. V. (2021) · Genes · doi:10.3390/genes13010080 · Cited by 8
Relationships between Circulating Sclerostin, Bone Marrow Adiposity, Other Adipose Deposits and Lean Mass in Post-Menopausal Women
Courtalin, M., Bertheaume, N., Badr, S., During, A., Lombardo, D., Deken, V., Cortet, B., Clabaut, A., & Paccou, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065922 · Cited by 8
“It was reported that different types of mutations in the SOST gene are responsible for Van Buchem disease and sclerosteosis, both of which are characterized by a considerable increase in bone mass [41].”
Background
Sclerostin deficiency effectively promotes bone morphogenetic protein‐2‐induced ectopic bone formation
Nakamura, K., Koide, M., Kobayashi, Y., Yamashita, T., Matsushita, M., Yasuda, H., Ishihara, Y., Yoshinari, N., & Udagawa, N. (2023) · Journal of Periodontal Research · doi:10.1111/jre.13134 · Cited by 8
Iguratimod suppresses sclerostin and receptor activator of NF-κB ligand production via the extracellular signal–regulated kinase/early growth response protein 1/tumor necrosis factor alpha pathway in osteocytes and ameliorates disuse osteoporosis in mice
Miura, T., Etani, Y., Noguchi, T., Hirao, M., Takami, K., Goshima, A., Kurihara, T., Fukuda, Y., Ochiai, N., Kanamoto, T., et al. (2024) · Bone · doi:10.1016/j.bone.2024.117026 · Cited by 10

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
DOI: 10.1093/hmg/10.5.537
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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Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)

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