The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
Socrates E Papapoulos - One of the best experts on this subject based on the ideXlab platform.
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patients with Sclerosteosis and disease carriers human models of the effect of sclerostin on bone turnover
Journal of Bone and Mineral Research, 2011Co-Authors: Antoon Van Lierop, H. Hamersma, Rutger L Van Bezooijen, J Power, N Loveridge, Neveen A T Hamdy, Socrates E PapapoulosAbstract:Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with Sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with Sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption.
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Sclerostin: Current Knowledge and Future Perspectives
Calcified Tissue International, 2010Co-Authors: M. J. C. Moester, Socrates E Papapoulos, Clemens W G M Lowik, R. L. BezooijenAbstract:In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias Sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with Sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.
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wnt but not bmp signaling is involved in the inhibitory action of sclerostin on bmp stimulated bone formation
Journal of Bone and Mineral Research, 2006Co-Authors: Rutger L Van Bezooijen, Peter J Svensson, Daniel Eefting, Annemieke Visser, Geertje Van Der Horst, Marcel Karperien, Paul H A Quax, Harry Vrieling, Socrates E PapapoulosAbstract:Sclerostin is an osteocyte-derived negative regulator of bone formation. It inhibits BMP-stimulated bone formation both in vitro and in vivo but has no direct effect on BMP signaling. Instead, sclerostin inhibits Wnt signaling that is required for BMP-stimulated osteoblastic differentiation. Introduction: Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize BMP activity. Sclerostin has been shown to inhibit BMP-stimulated bone formation, but its mechanism of action seems to be different from classical BMP antagonists. In this study, we investigated the mechanism by which sclerostin inhibits BMP-stimulated bone formation. Materials and Methods: DNA electroporation of calf muscle of mice using expression plasmids for BMP and sclerostin was used to study the effect of sclerostin on BMP-induced bone formation in vivo. Transcriptional profiling using microarrays of osteoblastic cells treated with BMP in the absence or presence of sclerostin was used to find specific growth factor signaling pathways affected by sclerostin. The affected pathways were further studied using growth factor-specific reporter constructs. Results: BMP-induced ectopic bone formation in calf muscle of mice was prevented by co-expression of sclerostin in vivo. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways. Sclerostin, however, did not inhibit stimulation of direct BMP target genes. Furthermore, we did not obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP-specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMP- and Wnt-induced Wnt reporter construct activation. Conclusions: Sclerostin inhibits BMP-stimulated bone formation but does not affect BMP signaling. Instead, it antagonizes Wnt signaling in osteoblastic cells. High bone mass in Sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling. © 2007 American Society for Bone and Mineral Research.
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bone mineral density in Sclerosteosis affected individuals and gene carriers
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jessica Gardner, Peter Beighton, H. Hamersma, Rutger L Van Bezooijen, Clemens W G M Lowik, Neveen A T Hamdy, Benjamin Mervis, Socrates E PapapoulosAbstract:Background: Sclerosteosis is an autosomal recessive sclerosing bone disorder due to deficiency of sclerostin, a protein secreted by the osteocytes that inhibits bone formation. In the present study we assessed the effect of variable expression of the genetic defect on bone mineral density (BMD) in patients and carriers of the determinant gene. Methods: We studied 25 individuals (seven patients and 18 phenotypically normal heterozygotes). BMD was measured by dual x-ray absorptiometry at the lumbar spine, total hip, and distal forearm, and lateral radiographs of the skull were obtained. Results: Individuals with Sclerosteosis had markedly increased BMD at all skeletal sites (Z-score ranges: lumbar spine, +7.73 to +14.43; total hip, +7.84 to +11.51; forearm, +4.44 to +9.53). In heterozygotes, BMD was above the mean value of healthy age-matched individuals at all skeletal sites and had a wide range of normal and clearly increased values. Skull radiographs showed the typical hyperostotic changes in affected in...
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sost sclerostin an osteocyte derived negative regulator of bone formation
Cytokine & Growth Factor Reviews, 2005Co-Authors: Rutger L Van Bezooijen, Socrates E Papapoulos, Peter Ten Dijke, Clemens W G M LowikAbstract:Sclerosteosis and Van Buchem disease are two closely related bone disorders characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is associated with mutations in the SOST gene and Van Buchem disease with a 52 kb deletion downstream of the SOST gene that probably affects transcription of the gene. Expression of the gene product sclerostin in bone is restricted to osteocytes and it is a negative regulator of bone formation. It inhibits BMP-stimulated bone formation, but cannot antagonize all BMP responses. The exclusive bone phenotype of good quality of patients with Sclerosteosis and Van Buchem disease and the specific localization of sclerostin make it an attractive target for the development of bone forming therapeutics.
Rutger L Van Bezooijen - One of the best experts on this subject based on the ideXlab platform.
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patients with Sclerosteosis and disease carriers human models of the effect of sclerostin on bone turnover
Journal of Bone and Mineral Research, 2011Co-Authors: Antoon Van Lierop, H. Hamersma, Rutger L Van Bezooijen, J Power, N Loveridge, Neveen A T Hamdy, Socrates E PapapoulosAbstract:Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with Sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with Sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption.
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osteocyte derived sclerostin inhibits bone formation its role in bone morphogenetic protein and wnt signaling
Journal of Bone and Joint Surgery American Volume, 2008Co-Authors: Peter Ten Dijke, David J J De Gorter, Carola Krause, Clemens W G M Lowik, Rutger L Van BezooijenAbstract:Sclerosteosis and Van Buchem disease are rare, high-bone-mass disorders that have been linked to deficiency in the SOST gene, encoding sclerostin. Sclerostin belongs to the DAN family of glycoproteins, of which multiple family members have been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity. Sclerostin is specifically expressed by osteocytes and inhibits BMP-induced osteoblast differentiation and ectopic bone formation. Sclerostin binds only weakly to BMPs and does not inhibit direct BMP-induced responses. Instead, sclerostin antagonizes canonical Wnt signaling by binding to Wnt coreceptors, low-density lipoprotein receptor-related protein 5 and 6. Several lipoprotein receptor-related protein-5 mutants that cause the high-bone-mass trait are defective in sclerostin binding. Thus, high bone mass in Sclerosteosis and Van Buchem disease may result from increased Wnt signaling due to the absence of or insensitivity to sclerostin.
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wnt but not bmp signaling is involved in the inhibitory action of sclerostin on bmp stimulated bone formation
Journal of Bone and Mineral Research, 2006Co-Authors: Rutger L Van Bezooijen, Peter J Svensson, Daniel Eefting, Annemieke Visser, Geertje Van Der Horst, Marcel Karperien, Paul H A Quax, Harry Vrieling, Socrates E PapapoulosAbstract:Sclerostin is an osteocyte-derived negative regulator of bone formation. It inhibits BMP-stimulated bone formation both in vitro and in vivo but has no direct effect on BMP signaling. Instead, sclerostin inhibits Wnt signaling that is required for BMP-stimulated osteoblastic differentiation. Introduction: Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize BMP activity. Sclerostin has been shown to inhibit BMP-stimulated bone formation, but its mechanism of action seems to be different from classical BMP antagonists. In this study, we investigated the mechanism by which sclerostin inhibits BMP-stimulated bone formation. Materials and Methods: DNA electroporation of calf muscle of mice using expression plasmids for BMP and sclerostin was used to study the effect of sclerostin on BMP-induced bone formation in vivo. Transcriptional profiling using microarrays of osteoblastic cells treated with BMP in the absence or presence of sclerostin was used to find specific growth factor signaling pathways affected by sclerostin. The affected pathways were further studied using growth factor-specific reporter constructs. Results: BMP-induced ectopic bone formation in calf muscle of mice was prevented by co-expression of sclerostin in vivo. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways. Sclerostin, however, did not inhibit stimulation of direct BMP target genes. Furthermore, we did not obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP-specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMP- and Wnt-induced Wnt reporter construct activation. Conclusions: Sclerostin inhibits BMP-stimulated bone formation but does not affect BMP signaling. Instead, it antagonizes Wnt signaling in osteoblastic cells. High bone mass in Sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling. © 2007 American Society for Bone and Mineral Research.
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bone mineral density in Sclerosteosis affected individuals and gene carriers
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jessica Gardner, Peter Beighton, H. Hamersma, Rutger L Van Bezooijen, Clemens W G M Lowik, Neveen A T Hamdy, Benjamin Mervis, Socrates E PapapoulosAbstract:Background: Sclerosteosis is an autosomal recessive sclerosing bone disorder due to deficiency of sclerostin, a protein secreted by the osteocytes that inhibits bone formation. In the present study we assessed the effect of variable expression of the genetic defect on bone mineral density (BMD) in patients and carriers of the determinant gene. Methods: We studied 25 individuals (seven patients and 18 phenotypically normal heterozygotes). BMD was measured by dual x-ray absorptiometry at the lumbar spine, total hip, and distal forearm, and lateral radiographs of the skull were obtained. Results: Individuals with Sclerosteosis had markedly increased BMD at all skeletal sites (Z-score ranges: lumbar spine, +7.73 to +14.43; total hip, +7.84 to +11.51; forearm, +4.44 to +9.53). In heterozygotes, BMD was above the mean value of healthy age-matched individuals at all skeletal sites and had a wide range of normal and clearly increased values. Skull radiographs showed the typical hyperostotic changes in affected in...
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sost sclerostin an osteocyte derived negative regulator of bone formation
Cytokine & Growth Factor Reviews, 2005Co-Authors: Rutger L Van Bezooijen, Socrates E Papapoulos, Peter Ten Dijke, Clemens W G M LowikAbstract:Sclerosteosis and Van Buchem disease are two closely related bone disorders characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is associated with mutations in the SOST gene and Van Buchem disease with a 52 kb deletion downstream of the SOST gene that probably affects transcription of the gene. Expression of the gene product sclerostin in bone is restricted to osteocytes and it is a negative regulator of bone formation. It inhibits BMP-stimulated bone formation, but cannot antagonize all BMP responses. The exclusive bone phenotype of good quality of patients with Sclerosteosis and Van Buchem disease and the specific localization of sclerostin make it an attractive target for the development of bone forming therapeutics.
Peter Beighton - One of the best experts on this subject based on the ideXlab platform.
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the clinical features of Sclerosteosis
Annals of Internal Medicine, 2020Co-Authors: Peter Beighton, Lecia Durr, H. HamersmaAbstract:Abstract Sclerosteosis is a unique autosomal recessive condition in which skeletal overgrowth is associated with syndactyly and digital malformation. Analysis of the course and clinical features in...
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Sclerosteosis an autosomal recessive disorder
Clinical Genetics, 2008Co-Authors: Peter Beighton, J S Davidson, Lecia Durr, Herman A HamersmaAbstract:: Sclerosteosis is a rare, potentially lethal skeletal disorder in which massive bony over-growth leads to facial distortion, cranial nerve compression and progressive rise in intracranial pressure. Gigantism and syndactyly of the 2nd and 3rd fingers are associated features. In a nationwide investigation in South Africa, 25 affected individuals in 15 Afrikaner kindreds have been studied. The minimum prevalence of the contition in this community is 1 in 75,000. Analysis of pedigree data confirms that Sclerosteosis is an autosomal recessive condition. The gene frequency in the Afrikaner people is estimated at 0.0035, with 10,000 clinically normal heterozygotes in this population. Heterozygote detection may be possible on a basis of recognition of minor changes which are apparent on skull radiographs.
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the syndromic status of Sclerosteosis and van buchem disease
Clinical Genetics, 2008Co-Authors: Peter Beighton, Herman A Hamersma, A Barnard, A Van Der WoudenAbstract:We have examined 50 persons with Sclerosteosis in the Afrikaner community of South Africa and I5 individuals with van Buchem disease in Holland. The clinical and radiographic manifestations of these conditions are very similar, the only notable differences being greater severity and syndactyly in the majority of the patients with Sclerosteosis. The Afrikaners have Dutch antecedants and it seems likely that these autosomal recessive disorders result from homozygosity of the same faulty genes. The phenotypic variation may be due to the epistatic effect of modifying genes in the Afrikaner population. Received 6 July, accepted for publication 27 September 1983
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bone mineral density in Sclerosteosis affected individuals and gene carriers
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jessica Gardner, Peter Beighton, H. Hamersma, Rutger L Van Bezooijen, Clemens W G M Lowik, Neveen A T Hamdy, Benjamin Mervis, Socrates E PapapoulosAbstract:Background: Sclerosteosis is an autosomal recessive sclerosing bone disorder due to deficiency of sclerostin, a protein secreted by the osteocytes that inhibits bone formation. In the present study we assessed the effect of variable expression of the genetic defect on bone mineral density (BMD) in patients and carriers of the determinant gene. Methods: We studied 25 individuals (seven patients and 18 phenotypically normal heterozygotes). BMD was measured by dual x-ray absorptiometry at the lumbar spine, total hip, and distal forearm, and lateral radiographs of the skull were obtained. Results: Individuals with Sclerosteosis had markedly increased BMD at all skeletal sites (Z-score ranges: lumbar spine, +7.73 to +14.43; total hip, +7.84 to +11.51; forearm, +4.44 to +9.53). In heterozygotes, BMD was above the mean value of healthy age-matched individuals at all skeletal sites and had a wide range of normal and clearly increased values. Skull radiographs showed the typical hyperostotic changes in affected in...
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the natural history of Sclerosteosis
Clinical Genetics, 2003Co-Authors: H. Hamersma, Jessica Gardner, Peter BeightonAbstract:Sclerosteosis (SCL) is a severe, progressive, autosomal-recessive craniotubular hyperostosis (MIM 269500). The determinant gene (SOST) has been isolated, and genotype-phenotype correlations, as well as the elucidation of pathogenetic mechanisms, are dependent upon the documentation of the natural history of the condition. For this reason, the course and complications in 63 affected individuals in South Africa, seen over a 38-year period, have been analyzed. Thirty-four of these persons died during the course of the survey, 24 from complications related to elevation of intracranial pressure as a result of calvarial overgrowth. The mean age of death in this group of individuals was 33 years, with an even gender distribution. Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons. Mandibular overgrowth was present in 46 (73%) adults and syndactyly in 48 (76%). In South Africa in 2002, 29 affected persons were alive, 10 being < or =20 years of age. It is evident that Sclerosteosis is a severe disorder which places a considerable burden upon affected individuals and their families.
Clemens W G M Lowik - One of the best experts on this subject based on the ideXlab platform.
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Sclerostin: Current Knowledge and Future Perspectives
Calcified Tissue International, 2010Co-Authors: M. J. C. Moester, Socrates E Papapoulos, Clemens W G M Lowik, R. L. BezooijenAbstract:In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias Sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with Sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.
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osteocyte derived sclerostin inhibits bone formation its role in bone morphogenetic protein and wnt signaling
Journal of Bone and Joint Surgery American Volume, 2008Co-Authors: Peter Ten Dijke, David J J De Gorter, Carola Krause, Clemens W G M Lowik, Rutger L Van BezooijenAbstract:Sclerosteosis and Van Buchem disease are rare, high-bone-mass disorders that have been linked to deficiency in the SOST gene, encoding sclerostin. Sclerostin belongs to the DAN family of glycoproteins, of which multiple family members have been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity. Sclerostin is specifically expressed by osteocytes and inhibits BMP-induced osteoblast differentiation and ectopic bone formation. Sclerostin binds only weakly to BMPs and does not inhibit direct BMP-induced responses. Instead, sclerostin antagonizes canonical Wnt signaling by binding to Wnt coreceptors, low-density lipoprotein receptor-related protein 5 and 6. Several lipoprotein receptor-related protein-5 mutants that cause the high-bone-mass trait are defective in sclerostin binding. Thus, high bone mass in Sclerosteosis and Van Buchem disease may result from increased Wnt signaling due to the absence of or insensitivity to sclerostin.
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bone mineral density in Sclerosteosis affected individuals and gene carriers
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jessica Gardner, Peter Beighton, H. Hamersma, Rutger L Van Bezooijen, Clemens W G M Lowik, Neveen A T Hamdy, Benjamin Mervis, Socrates E PapapoulosAbstract:Background: Sclerosteosis is an autosomal recessive sclerosing bone disorder due to deficiency of sclerostin, a protein secreted by the osteocytes that inhibits bone formation. In the present study we assessed the effect of variable expression of the genetic defect on bone mineral density (BMD) in patients and carriers of the determinant gene. Methods: We studied 25 individuals (seven patients and 18 phenotypically normal heterozygotes). BMD was measured by dual x-ray absorptiometry at the lumbar spine, total hip, and distal forearm, and lateral radiographs of the skull were obtained. Results: Individuals with Sclerosteosis had markedly increased BMD at all skeletal sites (Z-score ranges: lumbar spine, +7.73 to +14.43; total hip, +7.84 to +11.51; forearm, +4.44 to +9.53). In heterozygotes, BMD was above the mean value of healthy age-matched individuals at all skeletal sites and had a wide range of normal and clearly increased values. Skull radiographs showed the typical hyperostotic changes in affected in...
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sost sclerostin an osteocyte derived negative regulator of bone formation
Cytokine & Growth Factor Reviews, 2005Co-Authors: Rutger L Van Bezooijen, Socrates E Papapoulos, Peter Ten Dijke, Clemens W G M LowikAbstract:Sclerosteosis and Van Buchem disease are two closely related bone disorders characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is associated with mutations in the SOST gene and Van Buchem disease with a 52 kb deletion downstream of the SOST gene that probably affects transcription of the gene. Expression of the gene product sclerostin in bone is restricted to osteocytes and it is a negative regulator of bone formation. It inhibits BMP-stimulated bone formation, but cannot antagonize all BMP responses. The exclusive bone phenotype of good quality of patients with Sclerosteosis and Van Buchem disease and the specific localization of sclerostin make it an attractive target for the development of bone forming therapeutics.
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sclerostin is an osteocyte expressed negative regulator of bone formation but not a classical bmp antagonist
Journal of Experimental Medicine, 2004Co-Authors: Rutger L Van Bezooijen, H. Hamersma, Annemieke Visser, Marcel Karperien, Socrates E Papapoulos, Peter Ten Dijke, Bernard A J Roelen, Lianne Van Der Weepals, Edwin De Wilt, Clemens W G M LowikAbstract:Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.
Wendy Balemans - One of the best experts on this subject based on the ideXlab platform.
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a known sost gene mutation causes Sclerosteosis in a familial and an isolated case from brazilian origin
Genetic Testing, 2008Co-Authors: Chong Ae Kim, Wendy Balemans, Rachel Sayuri Honjo, Debora Romeo Bertola, Lilian Maria Jose Albano, Luiz Antonio Nunes De Oliveira, Sumatra Jales, Jose Tadeu Tesseroli De Siqueira, Arthur Menino Castilho, Elke PitersAbstract:Sclerosteosis is a severe, rare, autosomal recessive bone condition that is characterized by a progressive craniotubular hyperostosis. The main features are a significant sclerosis of the long bones, ribs, pelvis, and skull, leading to facial distortion and entrapment of cranial nerves. Clinical features include a tall stature, nail dysplasia, cutaneous syndactyly of some fingers, and raised intracranial pressure. The Sclerosteosis gene has been mapped to chromosome 17q12–21 and is currently known as the SOST gene encoding the sclerostin protein. Here, we report on one familial and one isolated case of Brazilian origin with the clinical and molecular diagnosis of Sclerosteosis. The radiological and clinical features are described, and the diagnosis of Sclerosteosis was confirmed in both cases by mutation analysis of the SOST gene showing a homozygous nonsense mutation (Trp124X) in the two patients. We reported this mutation previously in other Sclerosteosis patients from a consanguineous Brazilian family....
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a generalized skeletal hyperostosis in two siblings caused by a novel mutation in the sost gene
Bone, 2005Co-Authors: Wendy Balemans, Erna Cleiren, Ulrike Siebers, Jurgen Horst, Wim Van HulAbstract:In this study, a brother and sister of German origin are described with a possible diagnosis of van Buchem disease, a rare autosomal recessive sclerosing bone dysplasia characterized by a generalized hyperostosis of the skeleton mainly affecting the cranial bones. Clinically, patients suffer from cranial nerve entrapment potentially resulting in facial paresis, hearing disturbances, and visual loss. The radiological picture of van Buchem disease closely resembles Sclerosteosis, although in the latter patients, syndactyly, tall stature, and raised intracranial pressure are frequently observed, allowing a differential diagnosis with van Buchem disease. Previous molecular studies demonstrated homozygous loss-of-function mutations in the SOST gene in Sclerosteosis patients while a chromosomal rearrangement creating a 52-kb deletion downstream of this gene was found in Dutch patients with van Buchem disease. This deletion most likely suppresses SOST expression. Sclerostin, the SOST gene product, has been shown to play a role in bone metabolism. The two siblings reported here were evaluated at the molecular level by carrying out a mutation analysis of the SOST gene. This resulted in the identification of a novel putative disease-causing splice site mutation (IVS1 + 1 G→C) homozygously present in both siblings.
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identification of the disease causing gene in Sclerosteosis discovery of a novel bone anabolic target
Journal of Musculoskeletal & Neuronal Interactions, 2004Co-Authors: Wendy Balemans, W Van HulAbstract:Genetic studies recently unraveled the genetic cause of Sclerosteosis, a rare skeletal dysplasia characterized by a generalized increase in bone mass. Different loss-of-function mutations were identified in SOST, a gene with no homology to any known gene. This SOST gene is also involved in the pathogenesis of van Buchem disease, a disorder closely resembling Sclerosteosis, since a 52-kb deletion located downstream of SOST is found in patients diagnosed with this condition. Molecular studies showed a very restricted expression pattern of SOST and its gene product, sclerostin, with areas in the bone tissue, more precisely in cells of the osteoblast lineage, being the major sites of expression. Sclerostin is a secreted protein with a cysteine knot motif. In vitro studies demonstrated that sclerostin acts as a modulator of BMP signaling by binding to different members of the BMP growth factor family and acting on downstream BMP signal transduction events. The important function of sclerostin in bone metabolism has also been proven in vivo by the osteopenic phenotype of transgenic mice overexpressing SOST in bone. The identification of sclerostin as an important protein in bone metabolism opens new perspectives for the development of anabolic therapeutics to prevent and treat osteoporosis.
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identification of a 52 kb deletion downstream of the sost gene in patients with van buchem disease
Journal of Medical Genetics, 2002Co-Authors: Wendy Balemans, Frederik G Dikkers, Martin Ebeling, E Van Hul, M Dioszegi, C Lacza, Wim Wuyts, Neela Patel, P Hildering, Patrick J WillemsAbstract:Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of Sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in Sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred Sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and Sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in Sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.
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increased bone density in Sclerosteosis is due to the deficiency of a novel secreted protein sost
Human Molecular Genetics, 2001Co-Authors: Wendy Balemans, Jenneke Van Den Ende, Martin Ebeling, Neel Patel, E Van Hul, P Olson, M Dioszegi, C Lacza, Wim Wuyts, Patrick J WillemsAbstract: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 ~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.