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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Circulating sclerostin levels in relation to nutritional status, sex hormones and selected bone turnover biochemical markers levels in peri- and postmenopausal women
Czajkowska, M., Plinta, R., Owczarek, A. J., Olszanecka‐Glinianowicz, M., & Skrzypulec‐Plinta, V. (2019) · Ginekologia Polska · doi:10.5603/gp.2019.0064 · Cited by 5
Accelerated development of instability-induced osteoarthritis in transgenic mice overexpressing SOST.
Zhou, S., Ge, Y., Li, Y., Bao, Z., Chen, Y., Teng, H., & Jiang, Q. Y. (2017) · PubMed Central · Cited by 5
Targeting the Wnt signaling pathway for the development of novel therapies for osteoporosis
Yavropoulou, M. P., & Papapoulos, S. E. (2010) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.10.48 · Cited by 5
Recent progress in the molecular genetics of sclerosing bone dysplasias
Hul, W. V. (2003) · Fetal and Pediatric Pathology · doi:10.1080/15227950307696 · Cited by 5
Management of Osteoporosis: Who to Treat, What to Use, and for How Long?
Kim, S. W. (2013) · Korean Journal of Medicine · doi:10.3904/kjm.2013.85.4.364 · Cited by 5
New and emerging treatments for osteoporosis
Clarke, B. L. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03541.x · Cited by 5
Disorders of Bone Density, Volume, and Mineralization
Descartes, M. D., & Sillence, D. O. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-383834-6.00164-6 · Cited by 5
New Aspects of Genetic Basis, Classification and Treatment of Osteogenesis Imperfecta: Literature Review
Yakhyaeva, G. Т., Namazova-Baranova, L. S., & Margieva, T. V. (2015) · Педиатрическая фармакология · doi:10.15690/pf.v12i5.1461 · Cited by 5
“П Е Д И А ТР И Ч Е С К А Я Ф А Р М А К О Л О ГИ Я / 2 0 1 5 / ТО М 1 2 / No 5 розом и скелетными нарушениями, связанными с низкой костной массой, навели данные о патогенезе редких генетических заболеваний костей склеростеозисе [55] и болезни Ван Бухема.”
Reflecting on Some Discoveries of 40 Years and Their Outcomes
Martin, T. J. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3282 · Cited by 5
“Using positional cloning they identified the SOST gene to be mutated in osteosclerosis patients in a group of related subjects in the Netherlands.((54)) Inactivating mutations were also found in this gene in a group of affected Afrikaans subjects.”
Background
New agents for the treatment of osteoporosis
Martin, T. J., & Ng, K. W. (2007) · BoneKEy-Osteovision · doi:10.1138/20070279 · Cited by 5
“process (4), and the central role of certain genes in bone formation, revealed by genetic analysis of certain rare syndromes with skeletal phenotypes (5-8).”
Background
Mechanisms of Bone Remodeling
Shabestari, M., & Eriksen, E. F. (2013) · Osteoporosis · doi:10.1002/9781118316290.ch3 · Cited by 4
Recapitulating bone development events in a customised bioreactor through interplay of oxygen tension, medium pH, and systematic differentiation approaches
Lee, P. S., Hess, R., Friedrichs, J., Hänchen, V., Eckert, H., Cuniberti, G., Rancourt, D. E., Krawetz, R. J., Hintze, V., Gelinsky, M., et al. (2019) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2921 · Cited by 4
“Remarkably, these observations can be correlated to previous in vitro and in vivo reports that showed the suppressive effect of chronic acidosis on osteoblast development (Frick & Bushinsky, 2010) and Sost on the mineralisation mechanisms (Balemans, 2001; Poole et al., 2005).”
Result
Osteocytes
Bonewald, L. F. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-813073-5.00007-1 · Cited by 8
Sclerostin Antibody-Loaded Dense Collagen Hydrogels Promote Critical-Size Bone Defect Repair
Sicard, L., Maillard, S., Akoa, D. M., Torrens, C., Collignon, A.-M., Coradin, T., & Chaussain, C. (2024) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.4c00883 · Cited by 4
Wellbeing medicine: exercise, metabolic syndrome, and more
Stratakis, C. A. (2025) · HORMONES · doi:10.1007/s42000-025-00641-7 · Cited by 4
“Along these lines, maintaining bone health is also essential for health and longevity, and this is reviewed comprehensively by the story of sclerostin [5], a gene that my laboratory contributed to identifying back in 2001 [6].”
Association of total and bioactive serum sclerostin levels with bone metabolism in type 2 diabetes mellitus
Traechslin, C., Sewing, L., Baumann, S., Grize, L., Vavanikunnel, J., KRAENZLIN, M. E., Henzen, C., & Meier, C. (2025) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2025.100393 · Cited by 4
“Following the identification of the SOST gene, which encodes sclerostin [17], various methods have been used to measure sclerostin levels, including immunohistochemistry and Western blot analysis [18].”
Influential
The skeletal transcriptional response to mechanical load varies with age and tissue compartment in female mice
Chlebek, C., Raynor, M. S., Ross, F. P., & van der Meulen, M. C. H. (2025) · JBMR Plus · doi:10.1093/jbmrpl/ziaf105 · Cited by 3
Ligand–Receptor Interactions and Their Implications in Delivering Certain Signaling for Bone Regeneration
Katagiri, T., Tsukamoto, S., Osawa, K., & Kokabu, S. (2014) · Mechanical engineering series · doi:10.1007/978-3-319-13266-2_1 · Cited by 4
Unlocking the sost gene
Johnson, M. L. (2015) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2459 · Cited by 4
“Initially we had the identification of mutations in LRP5 that gave rise to both low((1)) and high bone mass (HBM),((2,3)) followed shortly thereafter by the identification of mutations causal for sclerosteosis((4,5)) and van Buchem disease((6,7)) that identified the SOST gene and its protein product sclerostin as impo…”
Background
Sclerosterosis (Truswell-Hansen disease)
Amalnath, S., & Vivekanandan, M. (2013) · Indian journal of human genetics · doi:10.4103/0971-6866.116109 · Cited by 4
“[3] Type 2 is due to mutation of LRP 4 gene [4] (low‑density lipoprotein receptor‑related protein) located at 11p11 Most of the reported patients of sclerosteosis are from the Afrikanar population [5] (descendants of the Dutch settlers) of South Africa.”
The Genetics of Peak Bone Mass
Gennari, L., Klein, R. F., & Ferrari, S. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374602-3.00012-2 · Cited by 4
Physiologic Actions of PTH I
Goltzman, D. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-397166-1.00009-6 · Cited by 4
Epigenetic Regulation of Sost/sclerostin Expression
del Real, Á., Riancho, J. A., & Delgado‐Calle, J. (2017) · Current Molecular Biology Reports · doi:10.1007/s40610-017-0063-9 · Cited by 5
“osteoblastogenesis, including miRNA-23, miRNA-30, miRNA-31, miRNA-34, miRNA-93, miRNA-103, miRNA125, miRNA-133, miRNA-135, miRNA-137, miRNA-145, miRNA-204, miRNA-205, miRNA-211, miRNA-214, miRNA-217, miRNA-218, miRNA-335, miRNA-338, miRNA-433, miRNA-637, and miRNA-3077 [78, 79, 92, 93]. Given the stimulatory effect of…”
Background
Bone metabolism
Kline, G. A., Orton, D. J., & Sadrzadeh, H. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803412-5.00004-5 · Cited by 4
Looking at Mountains: Role of Sustained Hypoxia in Regulating Bone Mineral Homeostasis in Relation to Wnt Pathway and Estrogen
Babu, L. K., & Ghosh, D. (2022) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-022-09283-4 · Cited by 4
All-trans Retinoic Acid and Beta-Carotene Increase Sclerostin Production in C2C12 Myotubes
Ewendt, F., Lehmann, A., Wodak, M. F., & Stangl, G. I. (2023) · Biomedicines · doi:10.3390/biomedicines11051432 · Cited by 4
“Notably, sclerostin, originally identified as an osteokine secreted by bone cells [12], was recently identified as a novel myokine through its expression and secretion by muscle cells [13].”
Background
Single-cell RNA-sequence analysis of human bone marrow reveals new targets for isolation of skeletal stem cells using spherical nucleic acids
Matthews, E., Lanham, S., White, K., Kyriazi, M. E., Alexaki, K., El-Sagheer, A. H., Brown, T. P., Kanaras, A. G., West, J. J., MacArthur, B. D., et al. (2023) · Journal of Tissue Engineering · doi:10.1177/20417314231169375 · Cited by 4
An Additional Lrp4 High Bone Mass Mutation Mitigates the Sost-Knockout Phenotype in Mice by Increasing Bone Remodeling
Hendrickx, G., Boudin, E., Mateiu, L. M., Yorgan, T. A., Steenackers, E., Kneissel, M., Krämer, I., Mortier, G. R., Schinke, T., & Hul, W. V. (2023) · Calcified Tissue International · doi:10.1007/s00223-023-01158-0 · Cited by 4
“Disease-causing variants have so far been identified in both SOST (MIM 269500) or LRP4 (MIM 614305) [4–6].”
Bone morphogenetic protein signaling is fine-tuned on multiple levels
Sieber, C., Schwaerzer, G. K., & Knaus, P. I. (2008) · Birkhäuser Basel eBooks · doi:10.1007/978-3-7643-8552-1_6 · Cited by 4
Cardio-ankle vascular index is linked to deranged metabolic status, especially high HbA1c and monocyte-chemoattractant-1 protein, in predialysis chronic kidney disease
Mert, M., Dursun, B., Yağcı, B., KARDEŞLER, A. Ç., Şenol, H., & Demir, S. (2019) · International Urology and Nephrology · doi:10.1007/s11255-019-02336-6 · Cited by 4
Bone Turnover Markers and Glucocorticoid Treatments
Devogelaer, J., Durnez, A., Gruson, D., & Manicourt, D. H. (2017) · Biomarkers in disease · doi:10.1007/978-94-007-7693-7_23 · Cited by 4
Removing the Bone Brake
Schett, G. A., & Bözec, A. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.08.009 · Cited by 4
“Sclerostin is the product of the SOST gene, which was found by geneticists in 2001 to be mutated in a few descendants of Dutch settlers in South Africa with excessively high bone mass (sclerostosis) (Balemans et al., 2001).”
Background
Mutations in sFRP1 or sFRP4 are not a common cause of craniotubular hyperostosis
Boudin, E., Piters, E., Fijałkowski, I., Stevenheydens, G., Steenackers, E., Kuismin, O., Moilanen, J. S., Mortier, G. R., & Hul, W. V. (2012) · Bone · doi:10.1016/j.bone.2012.09.034 · Cited by 4
“All other primers and methods used for mutation screening were previously described and are available on request [1,2,9,21].”
BackgroundMethod
Genes and osteoporosis: time for a change in strategy
Giroux, S., & Rousseau, F. (2009) · International Journal of Clinical Rheumatology · doi:10.2217/ijr.09.11 · Cited by 4
Production and Characterization of Monoclonal Antibodies to Human Sclerostin
Craig, T. A., Sommer, S. L., Beito, T. G., & Kumar, R. (2009) · Hybridoma · doi:10.1089/hyb.2009.0036 · Cited by 4
Biology, Physiology, and Morphology of Bone
Schett, G. A. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4377-1738-9.00004-9 · Cited by 4
Biology, Physiology, and Morphology of Bone
Rubin, J. E., & Rubin, C. T. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-3285-4.10004-x · Cited by 4

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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