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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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Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice
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“Encoded by the SOST gene, sclerostin is a glycoprotein secreted primarily by osteocytes under physiological conditions, and is a potent inhibitor of bone formation [13, 14].”
Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis
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Sclerostin: a possible target for the management of cancer-induced bone disease
Gkotzamanidou, M. A., Dimopoulos, M. A., Kastritis, E., Christoulas, D., Moulopoulos, L. A., & Terpos, E. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.697154 · Cited by 34
“In humans, SOST mRNA is detectable in tissues such as heart, aortic tissue, liver, odontoblasts and kidney; however, no sclerostin protein has been detected in any organs other than bone [1,10].”
BackgroundNovel insights on the effect of sclerostin on bone and other organs
Dreyer, T. J., Keen, J. A. C., Wells, L. M., & Roberts, S. J. (2023) · Journal of Endocrinology · doi:10.1530/joe-22-0209 · Cited by 36
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“Mutations in the Sost gene, such as in human diseases van Buchem disease and Sclerosteosis, result in high bone mass characteristics, primarily due to increased bone formation [11–14].”
BackgroundYavropoulou, M. P., Xygonakis, C., Lolou, M., Karadimou, F., & Yovos, J. G. (2014) · HORMONES · doi:10.14310/horm.2002.1552 · Cited by 35
“It is caused by a 52-kb deletion downstream of the SOST gene, which results in lack of a SOST-specific regulatory element and, like sclerosteosis, is an autosomal recessive disease.(5,19-21) All patients are homozygous for this deletion and have reduced levels of sclerostin, in contrast to sclerosteosis patients who h…”
BackgroundBiomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23
Mäkitie, R. E., Kämpe, A. J., Costantini, A., Alm, J. J., Magnusson, P., & Mäkitie, O. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3959 · Cited by 34
“Its aberrant activation has been demonstrated in several monogenic bone diseases with severe skeletal pathology; mutations in the transmembrane co-receptor low-density lipoprotein receptor-related protein 5 (LRP5) lead to osteoporosis-pseudoglioma syndrome and high bone mass disorder,((7)) and mutations in SOST, encod…”
BackgroundLin, C., Lin, R., Chang, C., Wang, G., & Lai, K. (2015) · Bioelectromagnetics · doi:10.1002/bem.21933 · Cited by 33
“Loss of function or deletion of the Sost gene leads to progressive bone overgrowths of these two diseases [Balemans et al., 1999, 2001; Brunkow et al., 2001].”
BackgroundSOST Inhibits Prostate Cancer Invasion
Hudson, B. D., Hum, N. R., Thomas, C. B., Kohlgruber, A. C., Sebastian, A., Collette, N. M., Coleman, M. A., Christiansen, B., & Loots, G. G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142058 · Cited by 35
“For example, loss- and gain-of function mutations in LRP5 cause either low or high bone mass [6, 7] and inactivation of SOST causes two hyperosteoses disorders: sclerosteosis [8, 9] and van Buchem's disease [10, 11].”
BackgroundLoots, G. G. (2008) · Advances in genetics · doi:10.1016/s0065-2660(07)00010-7 · Cited by 34
“They proceeded to show that a SOST wild-type allele expresses human SOST according to its endogenous expression pattern, primarily in the adult bone, while the VB allele fails to drive SOST expression in the bone.”
BackgroundInfluentialIdentification of a DNA aptamer that inhibits sclerostin's antagonistic effect on Wnt signalling
Shum, K. T., Chan, C., Leung, C.-M., & Tanner, J. A. (2011) · Biochemical Journal · doi:10.1042/bj20101096 · Cited by 33
“Loss of function mutations in the gene coding for sclerostin, SOST, result in the congenital disease sclerosteosis, characterised by strong and dense bone [1-4].”
BackgroundCirculating Sclerostin Levels and Markers of Bone Turnover in Chinese-American and White Women
Costa, A. G., Walker, M. D., Zhang, C. A., Cremers, S., Dworakowski, E., McMahon, D. J., Liu, C., & Bilezikian, J. P. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2106 · Cited by 32
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“Loss of function mutations in the sclerostin gene results in a high bonemass condition known as sclerosteosis [3,4] whereas a 52 kb deletion downstream of the gene leads to van Buchem's disease also associated with high bone mass [5,6].”
BackgroundThe Lrp4R1170Q Homozygous Knock-In Mouse Recapitulates the Bone Phenotype of Sclerosteosis in Humans
Boudin, E., Yorgan, T. A., Fijałkowski, I., Sonntag, S., Steenackers, E., Hendrickx, G., Peeters, S., Maré, A. D., Vervaet, B. A., Verhulst, A., et al. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3160 · Cited by 33
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Simão, M., & Cancela, M. L. (2021) · Biochemical Society Transactions · doi:10.1042/bst20200672 · Cited by 32
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“Their physiological importance has been confirmed by loss-offunction mutations in Sost, which cause high bone mass in humans (58, 59), whereas ablation of Sost or heterozygous deletion of Dkk1 causes high bone mass in mice (57, 60–62).”
BackgroundFunctional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies
Newnham, L. E., Wright, M., Holdsworth, G., Kostarelos, K., Robinson, M. K., Rabbitts, T. H., & Lawson, A. D. G. (2014) · mAbs · doi:10.4161/19420862.2015.989023 · Cited by 32
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“[3,4,5,6] Furthermore, several genome-wide association studies (GWAS) have identified LRP5 and other components of the WNT signaling pathway as major determinants of bone mass and fracture risk.”
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“Its biological importance in regulating bone mass in humans is highlighted by two genetic disorders associated with the loss of SOST expression, both with markedly increased bone mass: sclerosteosis, a progressive sclerosing bone dysplasia, and van Buchem disease, generalized bone overgrowth [106, 107].”
BackgroundPerspectives on osteoporosis therapies
Cairoli, E., Zhukouskaya, V. V., Eller-Vainicher, C., & Chiodini, I. (2015) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0236-9 · Cited by 32
“Furthermore, patients with homozygous genetic deficiency of sclerostin, but not those with heterozygous SOST mutation, present during growth bone overgrowth and skeletal deformity, especially of the skull and face, which can cause neurological complications [36–39].”
BackgroundRapid phenotyping of knockout mice to identify genetic determinants of bone strength
Freudenthal, B., Logan, J. G., _, _., Croucher, P. I., Williams, G. R., & Bassett, J. H. D. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0258 · Cited by 32
Kim, C. A., Honjo, R. S., Bertola, D. R., Albano, L. M. J., de Oliveira, L. R., Jales, S. M. D. C. P., Siqueira, J., Castilho, A. M., Balemans, W., Piters, E., et al. (2008) · Genetic Testing · doi:10.1089/gte.2008.0036 · Cited by 31
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“Sclerostin was discovered from genetic screenings of patients showing increased bone densities, revealing that patients suffering from van Buchem disease or Sclerosteosis lack or have decreased levels of Sclerostin [14,19].”
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de Castro, L. F., Maycas, M., Bravo, B., Esbrit, P., & Gortázar, A. R. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24734 · Cited by 31
“Osteocytes secrete sclerostin, a major inhibitor of Wnt/b-catenin pathway, which blocks osteoblast differentiation (Balemans et al., 2001; Loots et al., 2005).”
BackgroundSilverman, S. L. (2010) · Journal of Osteoporosis · doi:10.4061/2010/941419 · Cited by 30
“Loss-of-function mutations in SOST are associated with an autosomal-recessive disorder, sclerosteosis, which causes progressive bone overgrowth [4].”
BackgroundRemoli, C., Michienzi, S., Sacchetti, B., Consiglio, A. D., Cersosimo, S., Spica, E., Robey, P. G., Holmbeck, K., Cumano, A., BOYDE, A., et al. (2014) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2425 · Cited by 29
“These disorders represent the effects of loss-offunction mutations in SOST,((50,51)) a known Wnt inhibitor expressed in late stages of bone cell differentiation, which is otherwise known to be downregulated by agonists of the Gsa signaling pathway such as PTH.”
Glucocorticoids are not always deleterious for bone
van Lierop, A. H., Hamdy, N. A. T., & Papapoulos, S. E. (2010) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.151 · Cited by 30
“Van Buchem disease is thought to have milder clinical manifestations than sclerosteosis, a craniotubular hyperostosis with similar phenotype owing to inactivating mutations of the SOST gene.((6,7)) Management of the complications of both these sclerosing dysplasias is surgical, aiming at removal of the excess of bone,…”
BackgroundSclerostin and chronic kidney disease: the assay impacts what we (thought to) know
Delanaye, P., Paquot, F., Bouquegneau, A., Blocki, F. A., Krzesinski, J.-M., Evenepoel, P., Pottel, H., & Cavalier, E. (2017) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfx282 · Cited by 31
“Sclerostin, a 22-kDa protein secreted by osteocytes and chondrocytes, was originally described in humans with mutation of its producing gene (SOST), leading to a phenotype characterized by a high bone mass (sclerosteosis) [1].”
BackgroundFontalis, A., Kenanidis, E. I., Kotronias, R. A., Papachristou, A., Anagnostis, P. G., Potoupnis, M. E., & Tsiridis, E. E. (2019) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2019.1594772 · Cited by 31
“Another clinical and radiographical entity, caused by mutations in the SOST gene is sclerosteosis which is differentiated by van Buchem disease, by hand malformations and large stature [97].”
BackgroundOsteocytes and mechanical loading: The Wnt connection
Bullock, W. A., Pavalko, F. M., & Robling, A. G. (2019) · Orthodontics and Craniofacial Research · doi:10.1111/ocr.12282 · Cited by 31
“Moreover, loss of sclerostin either by mutations in the SOST coding sequence (10), or by deletion of downstream SOST enhancer regions (11), results in very high bone mass.”
BackgroundRare versus common diseases: a false dichotomy in precision medicine
Chung, B. H., Chau, J. F. T., & Wong, G. K. (2021) · npj Genomic Medicine · doi:10.1038/s41525-021-00176-x · Cited by 31
Baker, E. K., Taylor, S., Gupte, A., Chalk, A. M., Bhattacharya, S., Green, A. C., Martin, T. J., Strbenac, D., Robinson, M. D., Purton, L. E., et al. (2015) · Bone · doi:10.1016/j.bone.2014.12.063 · Cited by 30
“Of note, humans with sclerosteosis or the related van Buchem disease, both of which result frommutations reducing SOST expression or function, do not appear to be at increased risk of developing OS [17–22].”
BackgroundFazeli, P. K., Ackerman, K. E., Pierce, L., Guereca, G., Bouxsein, M., & Misra, M. (2013) · Osteoporosis International · doi:10.1007/s00198-013-2353-2 · Cited by 30
“Individuals with sclerosteosis have loss-of-function mutations in the sclerostin-encoding SOST gene and undetectable levels of sclerostin [7]; Nterminal propeptide of type 1 procollagen (P1NP), a marker of bone formation, and BMD are increased in individuals with sclerosteosis as compared to healthy controls [4, 7].”
Staines, K. A., Prideaux, M., Allen, S., Buttle, D. J., Pitsillides, A. A., & Farquharson, C. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.25282 · Cited by 30
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Novel approaches to the treatment of osteoporosis
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Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes
Maurel, D. B., Matsumoto, T., Vallejo, J. A., Johnson, M. L., Dallas, S. L., Kitase, Y., Brotto, M. A. P., Wacker, M., Harris, M. A., Harris, S. E., et al. (2019) · Bone Research · doi:10.1038/s41413-018-0037-4 · Cited by 29
Sclerostin expression in trabecular bone is downregulated by osteoclasts
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Fish Models of Induced Osteoporosis
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Insights Into the Mechanisms of Sclerostin Action in Regulating Bone Mass Accrual
Williams, B. O. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2154 · Cited by 28
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BackgroundCurrent and emerging therapies for the treatment of osteoporosis
Waalen, J. (2010) · Journal of Experimental Pharmacology · doi:10.2147/jep.s7823 · Cited by 29
“Sclerostin is the protein product of the SOST gene, mutations of which cause sclerosing bone diseases.(88,89) Decreased sclerostin secretion has been implicated as the signal for increasing Wnt pathway activity in mechanical stimulation of bone.”
Targeting the Wnt signaling pathway to augment bone formation
Shahnazari, M., Yao, W., Corr, M., & Lane, N. E. (2008) · Current Osteoporosis Reports · doi:10.1007/s11914-008-0025-5 · Cited by 29
“Sclerostin is the product of the Sost gene, which was originally identifi ed as the gene that, when mutated, causes sclerosteosis, a rare condition of progressive bone dysplasia characterized by a generalized skeletal overgrowth [ 42 ].”
BackgroundPeak Bone Mass and Its Regulation
Bonjour, J., Chevalley, T., Ferrari, S., & Rizzoli, R. (2011) · Elsevier eBooks · doi:10.1016/b978-0-12-382040-2.10009-7 · Cited by 30
Bone Response to Weight Loss Following Bariatric Surgery
Mele, C., Caputo, M., Ferrero, A., Daffara, T., Cavigiolo, B., Spadaccini, D., Nardone, A., Prodam, F., Aimaretti, G., & Marzullo, P. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.921353 · Cited by 37
Serum sclerostin levels in healthy men over 50 years of age
Bhattoa, H. P., Wamwaki, J., Kalina, E., Földesi, R., Balogh, Á. L., & Antal‐Szalmás, P. (2013) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-013-0451-z · Cited by 27
Toulis, K. A., Anastasilakis, A. D., Pοlyzos, S. A., & Makras, P. (2011) · HORMONES · doi:10.14310/horm.2002.1308 · Cited by 28
Agholme, F., Isaksson, H., Li, X., Ke, H. Z., & Aspenberg, P. (2011) · Acta Orthopaedica · doi:10.3109/17453674.2011.625539 · Cited by 29
“Sclerostin is an important negative regulator of bone, and naturally occurring mutations of the SOST gene in humans lead to the high bone mass condition sclerostosis (Balemans et al. 2001, Brunkow et al. 2001).”
A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders
Formosa, M. M., Bergen, D. J. M., Gregson, C. L., Maurizi, A., Kämpe, A. J., García‐Giralt, N., Zhou, W. Z., Grinberg, D., Ovejero, D., Zillikens, M. C., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.709711 · Cited by 28
“Loss-of-function (LoF) SOST variants cause sclerosteosis, a rare condition of excessive bone overgrowth (24); a 52-kb deletion located approximately 35-kb downstream of SOST is thought responsible for the milder phenotype of van Buchem’s disease (25, 26).”
BackgroundSclerostin is a promising therapeutic target for oral inflammation and regenerative dentistry
Liao, C., Liang, S., Wang, Y., Zhong, T., & Liu, X. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03417-4 · Cited by 32
“Sclerostin: a molecule that regulates bone metabolism The SOST gene is located in the human chromosomal region 17q12-q21, with only two exons and one intron [8, 9].”
BackgroundMabey, T., Honsawek, S., Tanavalee, A., Wilairatana, V., Yuktanandana, P., Saetan, N., & Zhan, D. (2014) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2014.03.011 · Cited by 28
“Inactivating mutations in the SOST gene can cause sclerosteosis and van Buchem disease which are bone dysplasia disorders characterized by progressive skeletal overgrowth [7–9].”
BackgroundEffects of Sclerostin Antibody on the Healing of Femoral Fractures in Ovariectomised Rats
Liu, Y., Rui, Y., Cheng, T.-Y., Huang, S., Xu, L., Meng, F., Lee, W., Zhang, T., Li, N., Li, C., et al. (2015) · Calcified Tissue International · doi:10.1007/s00223-015-0085-3 · Cited by 29
Minireview: Targeting the Wnt/-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton
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Osteoporosis treatment: bisphosphonates reign to continue for a few more years, at least?
Pazianas, M., & Abrahamsen, B. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13166 · Cited by 29
The effects of organic nitrates on osteoporosis: A systematic review
Jamal, S. A., Reid, L. S., & Hamilton, C. J. (2013) · Osteoporosis International · doi:10.1007/s00198-012-2262-9 · Cited by 27
“Individuals with congenital absence or reduction of circulating levels of sclerostin have very high bone mass [51].”
BackgroundWang, L., Yang, H., Huang, J., Pei, S., Wang, L., Feng, J. Q., Jing, D., Zhao, H., Kronenberg, H. M., Moore, D. C., et al. (2021) · Bone Research · doi:10.1038/s41413-020-00129-7 · Cited by 28
“Scale bar: 100 μm Bone Research (2021) 9:6 Bglap in SHP2-deficient OBs.”
BackgroundInfluentialGuo, L. Z., Iida, A., Bhavani, G. S., Gowrishankar, K., Wang, Z., Xue, J.-Y., Wang, J., Miyake, N., Matsumoto, N., Hasegawa, T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22340-8 · Cited by 27
“All animal experimental protocols were approved by the Animal Experiments Committee of the RIKEN Center for Integrative Medical Sciences (approval number: 2019-009(5)) and conformed to institutional guidelines for the study of vertebrates.”
MethodMechanisms of altered bone remodeling in children with type 1 diabetes
Brunetti, G., D’Amato, G., Santis, S. D., Grano, M., & Faienza, M. F. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i7.997 · Cited by 27
Advancing our understanding of osteocyte cell biology
Guo, D., & Bonewald, L. F. (2009) · Therapeutic Advances in Musculoskeletal Disease · doi:10.1177/1759720x09341484 · Cited by 27
“Research on sclerosteosis and van Buchem disease revealed mutations of a new gene named Sost responsible for the defects in these diseases [Balemans et al. 2001; Brunkow et al. 2001].”
BackgroundSclerostin measurement in human disease: Validity and current limitations
Costa, A. G., Cremers, S., & Bilezikian, J. P. (2016) · Bone · doi:10.1016/j.bone.2016.10.012 · Cited by 27
Shan, Y., Wang, L., Li, G., Shen, G., Zhang, P., & Xu, Y. (2018) · Biochemistry and Cell Biology · doi:10.1139/bcb-2018-0170 · Cited by 27
Kashii, M., Matuso, Y., Sugiura, T., Fujimori, T., Nagamoto, Y., Makino, T., Kaito, T., Ebina, K., Iwasaki, M., & Yoshikawa, H. (2015) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-015-0671-5 · Cited by 27
“In 2001 the SOST gene, which encodes sclerostin, was identified as the gene responsible for sclerosteosis [15, 16].”
BackgroundPathophysiology of Osteoporosis
Rodan, G. A., Raisz, L. G., & Bilezikian, J. P. (2002) · Elsevier eBooks · doi:10.1016/b978-012098652-1.50175-x · Cited by 27
Lane, N. E., & Silverman, S. L. (2010) · Current Osteoporosis Reports · doi:10.1007/s11914-010-0005-4 · Cited by 27
“5 or 5 mg with 200-mg CNAC; n=1 rhPTH [1-34]; n=1 placebo), three withdrew from prolonged vomiting (5-mg PTH [1–34] and 200-mg CNAC), and symptomatic but unconfirmed hypercalcemia (n=1 from the PTH [1–34] at 2.”
BackgroundSclerostin binds and regulates the activity of cysteine-rich protein 61
Craig, T. A., Bhattacharya, R., Mukhopadhyay, D., & Kumar, R. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.12.143 · Cited by 25
“Mutations within the sclerostin gene (SOST) are associated with sclerosteosis (MIM # 269500) or with van Buchem’s disease (MIM # 239100) [7].”
BackgroundRelative influence of heritability, environment and genetics on serum sclerostin
Kuipers, A. L., Zhang, Y., Yu, S., Kammerer, C. M., Nestlerode, C. S., Chu, Y., Bunker, C. H., Patrick, A. L., Wheeler, V. W., Miljkovic, I., et al. (2013) · Osteoporosis International · doi:10.1007/s00198-013-2517-0 · Cited by 26
Boudin, E., & Hul, W. V. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.06.003 · Cited by 29
Alonso, N., Estrada, K., Albagha, O., Herrera, L., Reppe, S., Olstad, O. K., Gautvik, K. M., Ryan, N., Evans, K. L., Nielson, C. M., et al. (2017) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-212469 · Cited by 26
Klein‐Nulend, J., & Bonewald, L. F. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373884-4.00028-8 · Cited by 26
Tan, C. O., Battaglino, R. A., Doherty, A., Gupta, R., Lazzari, A. A., Garshick, E., ZAFONTE, R. D., & Morse, L. R. (2014) · Osteoporosis International · doi:10.1007/s00198-014-2786-2 · Cited by 26
“Animal models have shown that limb unloading results in immediate osteocyte and osteoblast apoptosis [4] and increased osteoclastic bone resorption with reduced bone formation [5].”
BackgroundUnveiling the mysteries of the genetics of osteoporosis
Alonso, N., & Ralston, S. H. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0149-7 · Cited by 25
“Parametric linkage analysis has been highly successful in bone diseases which show a Mendelian pattern of inheritance (Table 1) [14–28].”
BackgroundZhu, L., Su, G., Dai, J. M., Zhang, W., Yin, C., Zhang, F.-Y., Zhu, Z., Guo, Z., Fang, J., Zou, C., et al. (2018) · Genomics · doi:10.1016/j.ygeno.2018.02.006 · Cited by 25
Frizzled‐4 is required for normal bone acquisition despite compensation by Frizzled‐8
Kushwaha, P., Kim, S., Foxa, G. E., Michalski, M. N., Williams, B. O., Tomlinson, R. E., & Riddle, R. C. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29563 · Cited by 25
“(Balemans et al., 2001; Balemans et al., 2002; Brunkow et al., 2001), a secreted inhibitor of Wnt/β‐catenin signaling (Li et al.”
The Cells of Bone and Their Interactions
Ansari, N., & Sims, N. A. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_343 · Cited by 29
Li, F., Li, P., Li, L., Deng, Y., Hu, Y., & He, B. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.608544 · Cited by 25
“Several skeletal diseases are due to aberrant Wnt/βcatenin signaling, such as tetra-amelia syndrome, autosomal recessive osteoporosis pseudoglioma syndrome, and sclerosteosis (Balemans et al., 2001; Gong et al., 2001; Niemann et al., 2004).”
BackgroundVollersen, N., Zhao, W., Rolvien, T., Lange, F., Schmidt, F. N., Sonntag, S., Shmerling, D., Kroge, S. V., Stockhausen, K. E., Sharaf, A. L., et al. (2021) · Bone Research · doi:10.1038/s41413-021-00170-0 · Cited by 25
“In these patients, either activating mutations of the putative WNT coreceptor LRP5 or inactivating mutations of the secreted protein sclerostin were identified as disease-causing.(5,6) It was subsequently found that sclerostin binds to LRP5 to antagonize WNT signaling and thereby bone formation and that high bone mass…”
BackgroundThe effect of osteoporosis treatment on bone mass
Appelman‐Dijkstra, N. M., Oei, H. L. D. W., Veldhuis‐Vlug, A. G., & Winter, E. M. (2022) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2022.101623 · Cited by 27
Novel SOST gene mutation in a sclerosteosis patient and her parents
Bhadada, S. K., Rastogi, A., Steenackers, E., Boudin, E., Arya, A. K., Dhiman, V., Bhansali, A., & Hul, W. V. (2012) · Bone · doi:10.1016/j.bone.2012.10.009 · Cited by 25
“Previously, six different mutations have been identified in the SOST gene underlying sclerosteosis from different geographical regions, which include one missense [13], two splice site [9,11], and three nonsense mutations [9,10,12] (Table 1) (Fig.”
BackgroundCremers, S., & Aronson, J. (2017) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13331 · Cited by 24
Sclerostin: an Emerging Target for the Treatment of Cancer-Induced Bone Disease
McDonald, M. M., & Delgado‐Calle, J. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0403-y · Cited by 25
Ye, W., Wang, Y., Mei, B., Hou, S., Liu, X., Wu, G., Qin, L., Zhao, K., & Huang, Q. (2018) · Bone · doi:10.1016/j.bone.2018.01.001 · Cited by 25
Buschke-Ollendorff syndrome: A manifestation of a heterozygous nonsense mutation in the LEMD3 gene
Gass, J. K., Hellemans, J., Mortier, G. R., Griffiths, M. H. G., & Burrows, N. (2008) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2007.03.031 · Cited by 25
Emerging pharmacologic therapies for osteoporosis
Grey, A. B. (2007) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.12.3.493 · Cited by 26
“Thus, deletion of the gene encoding sclerostin is associated with increased bone mass [124,125] and forced overexpression of sclerostin causes osteoporosis [123] .”
BackgroundDiegel, C. R., Krämer, I., Moes, C., Foxa, G. E., McDonald, M. J., Madaj, Z., Guth, S., Liu, J., Harris, J. L., Kneissel, M., et al. (2023) · Bone Research · doi:10.1038/s41413-023-00278-5 · Cited by 25
“4,18,19,36,37 Subsequent work showed that subjects either completely lacking SOST expression (sclerosteosis 6,38 ) or having severely diminished SOST expression due to loss of a regulatory enhancer sequence that acted on the SOST promoter (van Buchem disease 39 ) also developed extremely high bone…”
BackgroundLessons from rare diseases of cartilage and bone
Gallagher, J. A., Ranganath, L. R., & BOYDE, A. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.04.002 · Cited by 24
Role of sclerostin in the pathogenesis of chronic kidney disease-mineral bone disorder
Asamiya, Y., Tsuchiya, K., & Nitta, K. (2016) · Renal Replacement Therapy · doi:10.1186/s41100-016-0024-4 · Cited by 24
“Additional studies are needed to determine Osteoid New bone Old bone HSC Bone marrow MSC Wnt Wnt Wnt Wnt Wnt SOST SOST Dkk 1 Dkk 1 RANK Monocyte RANKL RANKL OPG Osteoblast Osteocyte Mature osteoblast Lining cell Apoptosis Matrix mineralization ?”
BackgroundLhaneche, L., Hald, J. D., Domingues, A., Hannouche, D., Délepine, M., Zélénika, D., Boland, A., Ostertag, A., Cohen-Solal, M. E., Langdahl, B. L., et al. (2016) · Bone · doi:10.1016/j.bone.2016.08.004 · Cited by 24
Positive and Negative Regulators of Sclerostin Expression
Iwamoto, R., Koide, M., Udagawa, N., & Kobayashi, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094895 · Cited by 27
“reported one splicing mutation and two nonsense mutations in the second exon [20].”
BackgroundSclerostin and Cardiovascular Disease
Tobias, J. H. (2023) · Current Osteoporosis Reports · doi:10.1007/s11914-023-00810-w · Cited by 26
Liu, X., Li, C., Liu, K., Cai-yan, C., Zhang, Y., & Liu, Y. (2012) · Biological Trace Element Research · doi:10.1007/s12011-012-9333-9 · Cited by 24
Developments in the scientific understanding of osteoporosis
Lane, N. E., & Yao, W. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2656 · Cited by 23
Osteocytes: Mechanosensors of Bone and Orchestrators of Mechanical Adaptation
Klein‐Nulend, J., & Bakker, A. D. (2007) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-008-9014-6 · Cited by 25
“Transgenic mice lacking sclerostin exhibit an increased bone mass, and the human condition of sclerostosis is due to a premature termination of the Sost gene [ 29 ], suggesting that sclerostin inhibits bone mass accrual.”
BackgroundJia, H., Ma, J. X., L., X., Yu, J. T., Feng, R., Xu, L. Y., Wang, J., Xing, D., Zhu, S., & Wang, Y. (2014) · Osteoporosis International · doi:10.1007/s00198-014-2818-y · Cited by 26
“The secreted sclerostin protein is the product of the SOST gene; in sclerosteosis and Van Buchem disease, the sclerostin level is dramatically decreased [1, 3, 4].”
BackgroundRudmann, D. G., Page, T. J., Vahle, J. L., Chouinard, L., Hailé, S., Poitout, F. M., Baskin, G. B., Lambert, A.-J., Walker, P., Glazier, G., et al. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr318 · Cited by 24
“Two rare clinical conditions of bone disease, sclerosteosis (SCL) and van Buchem disease, have been linked to alterations in SOST expression (Balemans et al., 2001, 2002; Bruknow et al., 2001; Staehling-Hampton et al., 2002).”
Background
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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