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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“mRNA expression was reported as relative expression (2), normalized to Tbp.”
Background
Systemic administration of sclerostin monoclonal antibody accelerates fracture healing in the femoral osteotomy model of young rats
Feng, G., Zhang, C., Yi-Min, C., & Li, X. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.11.010 · Cited by 41
New Treatment Modalities in Osteoporosis
CANALIS, E. M. (2010) · Endocrine Practice · doi:10.4158/ep10048.ra · Cited by 42
The sclerostin-bone protein interactome
Ketha, H., Craig, T. A., Madden, B. J., Bergen, H. R., & Kumar, R. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.12.048 · Cited by 41
“the regulation of osteoblastic activity [1,2,3,4,5].”
Background
Wnt signaling, a novel pathway regulating blood pressure? State of the art review
Ziki, M. D. A., & Mani, A. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.05.001 · Cited by 41
“Mutations in the Wnt pathway have been associated with multiple developmental disorders such as Fuhrman syndrome (25), Tetra-amelia syndrome (26), caudal duplication syndrome (27), sclerosteosis (28), and familial exudative vitreo-retinopathy (29) among others.”
Background
Molecular and radiological diagnosis of sclerosing bone dysplasias
Hul, W. V., Vanhoenacker, F. M. H. M., Balemans, W., Janssens, K., & de Schepper, A. M. (2001) · European Journal of Radiology · doi:10.1016/s0720-048x(01)00400-4 · Cited by 41
“Mutation analysis of the same gene in van Buchem patients could not reveal any mutations so far [38] but small rearrangements or mutations in cis-acting regions influencing the expression of the SOST gene cannot be excluded.”
BackgroundSelf-citation
Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis
Martin, T. J., Sims, N. A., & Ng, K. W. (2008) · Osteoporosis International · doi:10.1007/s00198-008-0575-5 · Cited by 42
“Sclerosteosis is a more severe skeletal phenotype than Van Buchem disease, but positional cloning revealed each to be caused by loss-of-function mutations in SOST [88].”
Background
MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation
Boudin, E., & Hul, W. V. (2017) · European Journal of Endocrinology · doi:10.1530/eje-16-0990 · Cited by 42
Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein
Gould, N. R., Williams, K. M., Joca, H. C., Torre, O. M., Lyons, J. S., Leser, J. M., Srikanth, M. P., Hughes, M., Khairallah, R. J., Feldman, R. A., et al. (2021) · eLife · doi:10.7554/elife.64393 · Cited by 40
New insights into the location and form of sclerostin
Hernández, P., Whitty, C., Wardale, R. J., & HENSON, F. M. D. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.03.079 · Cited by 40
Sclerostin Antibody Preserves the Morphology and Structure of Osteocytes and Blocks the Severe Skeletal Deterioration After Motor-Complete Spinal Cord Injury in Rats
Qin, W., Li, X., Peng, Y., Harlow, L. M., Ren, Y., Wu, Y., Li, J., Qin, Y., Sun, J., Zheng, S., et al. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2864 · Cited by 39
LRP5, serotonin, and bone: Complexity, contradictions, and conundrums
Goltzman, D. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.462 · Cited by 39
Carbonic anhydrase III protects osteocytes from oxidative stress
Shi, C., Uda, Y., Dedic, C., Azab, E., Sun, N., Hussein, A. I., Petty, C. A., Fulzele, K. S., Mitterberger, M. C., Zwerschke, W., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201700485rr · Cited by 39
Sclerostin-Neutralizing Antibody Enhances Bone Regeneration Around Oral Implants
Yu, S. H., Hao, J., Fretwurst, T., Liu, M., Kostenuik, P. J., Giannobile, W. V., & Jin, Q. (2018) · Tissue Engineering Part A · doi:10.1089/ten.tea.2018.0013 · Cited by 41
The osteocyte as a therapeutic target in the treatment of osteoporosis
Rochefort, G. Y. (2014) · Therapeutic Advances in Musculoskeletal Disease · doi:10.1177/1759720x14523500 · Cited by 40
“In humans, SOST mRNA is detectable in tissues such as heart, aorta, liver, odontoblasts, and kidney, whereas sclerostin protein has never been detected in any organs other than bone [Balemans et al. 2001; Moester et al. 2010].”
Background
Artifacts and Incidental Findings Encountered on Dual-Energy X-Ray Absorptiometry: Atlas and Analysis
Martineau, P., Bazarjani, S., & Zuckier, L. S. (2015) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2015.02.001 · Cited by 38
Sclerostin monoclonal antibody therapy with AMG 785: a potential treatment for osteoporosis
Lewiecki, E. M. (2010) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2011.540565 · Cited by 38
“Sclerostin is a SOST gene product that is a 190-residue secreted monomeric glycoprotein containing a cystine knotlike domain with homology to the Cerebrus/DAN family of bone morphogenetic protein (BMP) antagonists [59-61].”
Background
Immunohistochemical evidence for sclerostin during cementogenesis in mice
Lehnen, S. D. M., Götz, W., Baxmann, M., & Jäger, A. (2012) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2012.02.014 · Cited by 38
Sclerostin Expression in Bile Ducts of Patients With Chronic Cholestasis May Influence the Bone Disease in Primary Biliary Cirrhosis
Guañabens, N., Ruiz-Gaspà, S., Gifre, L., Miquel, R., Peris, P., Monegal, A., Dubrueil, M., Arias, A., & Parés, A. R. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2845 · Cited by 40
“Interestingly, isolated studies have shown that SOST, the gene encoding sclerostin, is also expressed in other tissues such as the cartilage, aorta, kidney, and in small quantities in the liver, among others, when human tissues and cell lines were examined.((24,25)) Furthermore, extraskeletal sources of sclerostin hav…”
Background
How Accurate is Your Sclerostin Measurement? Comparison Between Three Commercially Available Sclerostin ELISA Kits
Piec, I., Washbourne, C. J., TANG, J. C. Y., Fisher, E., Greeves, J. P., Jackson, S., & Fraser, W. D. (2016) · Calcified Tissue International · doi:10.1007/s00223-015-0105-3 · Cited by 37
“Sclerostin was discovered as a product of the SOST gene causing sclerosteosis [1, 2], and van Buchem syndrome [3, 4], and later confirmed in mice in which the SOST gene had been deleted [5] or overexpressed [6].”
Background
Lipoprotein receptor–related protein 6 is required for parathyroid hormone–induced Sost suppression
Li, C., Wang, W., Xie, L., Luo, X., Cao, X., & Wan, M. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12750 · Cited by 37
The Wnt Co-Receptor Lrp5 Is Required for Cranial Neural Crest Cell Migration in Zebrafish
Willems, B., Tao, S., Yu, T., Huysseune, A., Witten, P. E., & Winkler, C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131768 · Cited by 37
Association of circulating sclerostin with vascular calcification in Afro-Caribbean men
Kuipers, A. L., Miljkovic, I., Carr, J. J., Terry, J. G., Nestlerode, C. S., Ge, Y., Bunker, C. H., Patrick, A. L., & Zmuda, J. M. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.01.010 · Cited by 36
Sclerostin and skeletal health
Sharifi, M., Ereifej, L. K., & Lewiecki, E. M. (2015) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-015-9311-6 · Cited by 37
“This concept is supported by studies in mice showing increased BMD with anti-sclerostin antibody therapy [22].”
Zoledronic Acid Acutely Increases Sclerostin Serum Levels in Women With Postmenopausal Osteoporosis
Catalano, A., Morabito, N., Basile, G., Brancatelli, S., Cucinotta, D., & Lasco, A. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4039 · Cited by 36
“Moreover, in humans, sclerosteosis and Van Buchem disease are 2 rare autosomal recessive sclerosing bone disorders with closely related phenotypes associated with defective sclerostin production and characterized by severe lifelong bone overgrowth of the entire skeleton (6, 7).”
Background
Signaling Pathways in Craniofacial Development
Neben, C. L., & Merrill, A. E. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2015.09.005 · Cited by 36
“…between these high bone mass disorders and sclerosteosis, a disorder recognized a year earlier to be caused by nonsense mutations in a novel gene called SCLEROSTIN (SOST), led to the discovery that SOST is a WNT antagonist (Balemans et al., 2001; Brunkow et al., 2001; Semenov, Tamai, & He, 2005).”
Background
Postnatal β-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation
Kang, K. S., Hong, J. M., & Robling, A. G. (2016) · Bone · doi:10.1016/j.bone.2016.04.028 · Cited by 38
“The importance of Wnt signaling in bone metabolism has been demonstrated in many clinical contexts; for example, the high-bone-mass (HBM) phenotypes in patients with activating mutations in the Wnt coreceptors Lrp5 [10] and Lrp4 [11], the HBM phenotypes in patients with inactivating mutations in the Lrp5/6 inhibitor S…”
Influential
Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by spinal cord injury
Qin, W., Zhao, W., Li, X., Peng, Y., Harlow, L. M., Li, J., Qin, Y., Pan, J., Wu, Y., Ran, L., et al. (2016) · Osteoporosis International · doi:10.1007/s00198-016-3700-x · Cited by 36
Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo
Bullock, W. A., Hoggatt, A. M., Horan, D. J., Elmendorf, A. J., Sato, A. Y., Bellido, T., Loots, G. G., Pavalko, F. M., & Robling, A. G. (2019) · iScience · doi:10.1016/j.isci.2019.09.023 · Cited by 36
“Patients with homozygous loss-of-function mutations in Sost have sclerosteosis, characterized by dramatically increased bone mass and density (Balemans et al., 2001, 2002; Staehling-Hampton et al., 2002).”
Background
Romosozumab: a novel bone anabolic treatment option for osteoporosis?
Kerschan‐Schindl, K. (2019) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-019-00721-5 · Cited by 35
Serum sclerostin levels decline in post-menopausal women with osteoporosis following treatment with intermittent parathyroid hormone.
Piemonte, S., Romagnoli, E., Bratengeier, C., Woloszczuk, W., Tancredi, A., Pepe, J., Cipriani, C., & Minisola, S. (2012) · PubMed · doi:10.3275/8522 · Cited by 36
Energy Metabolism of Osteocytes
Karthik, V., & Guntur, A. R. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-021-00688-6 · Cited by 40
Hereditary Metabolic Bone Diseases: A Review of Pathogenesis, Diagnosis and Management
Charoenngam, N., Nasr, A., Shirvani, A., & Holick, M. F. (2022) · Genes · doi:10.3390/genes13101880 · Cited by 39
“This condition has been linked to autosomal recessive loss-of-function mutations in the SOST gene, encoding the protein sclerostin, which inhibits osteoblastic activity and suppresses bone formation by antagonizing the Wnt/β-catenin signaling pathway [61,62].”
Background
Time-dependent effects of sclerostin antibody on a mouse fracture healing model.
Cui, L., Cheng, H., Song, C., Li, C., Simonet, W. S., Ke, H. Z., & Li, G. (2013) · PubMed · Cited by 36
Investigational anabolic therapies for osteoporosis
Trivedi, R., Goswami, R., & Chattopadhyay, N. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.501077 · Cited by 35
“Conversely, high bone density in Van Buchem disease is caused by an inactivating mutation in the SOST gene [59].”
Background
Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta
Little, D. G., Peacock, L., Mikulec, K., Kneissel, M., Krämer, I., Cheng, T. L., Schindeler, A., & Munns, C. F. (2017) · Bone · doi:10.1016/j.bone.2017.04.016 · Cited by 35
Romosozumab (sclerostin monoclonal antibody) for the treatment of osteoporosis in postmenopausal women: A review
Shakeri, A., & Adanty, C. (2020) · Journal of Population Therapeutics & Clinical Pharmacology · doi:10.15586/jptcp.v27i1.655 · Cited by 35
Rare variations in WNT3A and DKK1 may predispose carriers to primary osteoporosis
Korvala, J., Löija, M., Mäkitie, O., Sochett, E. B., Jüppner, H., Schnabel, D., Mora, S., Cole, W. G., Ala‐Kokko, L., & Männikkö, M. (2012) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2012.06.011 · Cited by 35
Physical activity in relation to serum sclerostin, insulin-like growth factor-1 and bone turnover markers in healthy premenopausal women: A cross-sectional and a longitudinal study
Ardawi, M. S., Rouzi, A. A., & Qari, M. H. (2012) · Bone · doi:10.1016/j.bone.2012.02.092 · Cited by 35
Sclerostin: From Molecule to Clinical Biomarker
Omran, A. S., Atanasova, D., Landgren, F., & Magnusson, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094751 · Cited by 44
“The product of SOST, sclerostin, is a 24 kDa and 213 amino acid-long glycoprotein with a secretion signaling peptide comprising the first 23 amino acids [5].”
BackgroundInfluential
Update on romosozumab: a humanized monoclonal antibody to sclerostin
Costa, A. G., Bilezikian, J. P., & Lewiecki, E. M. (2014) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2014.895808 · Cited by 34
“Sclerostin contains 190 amino-acid residues with a cysteine knot-like domain that is characteristic of the Cerebeus/DAN family of glycoproteins [16-18], which are antagonists of bone morphogenetic protein (BMP) signaling.”
Background
Spinal Cord Injury and Osteoporosis: Causes, Mechanisms, and Rehabilitation Strategies
Tan, C. O. (2013) · International Journal of Physical Medicine & Rehabilitation · doi:10.4172/2329-9096.1000127 · Cited by 34

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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