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Vincent Brandenburg - One of the best experts on this subject based on the ideXlab platform.
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mendelian randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures
Journal of Bone and Mineral Research, 2019Co-Authors: Jie Zheng, Vincent Brandenburg, Christiane Drechsler, Christoph Wanner, Winfried Maerz, Ingrid Gergei, Marcus E Kleber, Sjur ReppeAbstract:In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (β = 0.20, p = 4.6 × 10-49 ) and GALNT1 (β = 0.11 per G allele, p = 4.4 × 10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (β = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (β = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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mendelian randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures
bioRxiv, 2019Co-Authors: Jie Zheng, Vincent Brandenburg, Christiane Drechsler, Christoph Wanner, Winfried Maerz, Ingrid Gergei, Marcus E Kleber, Sjur ReppeAbstract:ABSTRACT In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6×10−49), and GALNT1 (β=0.11 per G allele, P=4.4×10−11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= −0.12, 95%CI= −0.20 to −0.05) and eBMD (β= −0.12, 95%CI= −0.14 to −0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.
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genome wide mapping identifies beta 1 4 n acetyl galactosaminyl transferase as a novel determinant of sclerostin levels and bone mineral density
bioRxiv, 2018Co-Authors: Jie Zheng, Vincent Brandenburg, Christiane Drechsler, Christoph Wanner, Winfried Maerz, Ingrid Gergei, Marcus E Kleber, Sjur Reppe, Kaare M Gautvik, Carolina MedinagomezAbstract:ABSTRACT In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Sclerostin is also present at detectable concentrations within the circulation. Our genome wide association study (GWAS) meta-analysis of 10,584 European-descent individuals identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD) change in sclerostin per A allele β=0.20, P=4.6x10-49), and GALNT1 (β=0.11 per G allele, P=4.4x10-11), of which the former is a known locus for BMD estimated by heel ultrasound (eBMD). Common variants across the genome explained 16% of the phenotypic variation of serum sclerostin. Mendelian randomization revealed an inverse causal relationship between serum sclerostin and femoral neck BMD and eBMD, and a positive relationship with fracture risk. Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower BMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Renal and cortical bone tissue, and osteoblast cultures, were found to express high levels of B4GALNT3, an N-acetylgalactosaminyltransferase which adds a terminal LacdiNAc disaccharide to target glycocoproteins. Together, these findings raise the possibility that sclerostin is a substrate for B4GALNT3, such that its modification leads to higher levels, possibly through greater stability. GALNT1, an enzyme causing mucin-type O-linked glycosylation, may act in a similar capacity. We conclude that genetic variation in glycosylation enzymes represents a novel determinant of BMD and fracture risk, acting via alterations in levels of circulating sclerostin.
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from skeletal to cardiovascular disease in 12 steps the evolution of sclerostin as a major player in ckd mbd
Pediatric Nephrology, 2016Co-Authors: Vincent Brandenburg, Annika Deck, Djalila Mekahli, Björn Meijers, Ellen Neven, Patrick C Dhaese, Pieter EvenepoelAbstract:Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease – mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease—the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.
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increased circulating sclerostin levels in end stage renal disease predict biopsy verified vascular medial calcification and coronary artery calcification
Kidney International, 2015Co-Authors: Abdul Rashid Qureshi, Bengt Lindholm, Mathias Haarhaus, Vincent Brandenburg, Hannes Olauson, Anna Witasp, Annika Wernerson, Magnus Soderberg, Lars Wennberg, Louise NordforsAbstract:Sclerostin, an osteocyte-derived inhibitor of bone formation, is linked to mineral bone disorder. In order to validate its potential as a predictor of vascular calcification, we explored associations of circulating sclerostin with measures of calcification in 89 epigastric artery biopsies from patients with end-stage renal disease. Significantly higher sclerostin levels were found in the serum of patients with epigastric and coronary artery calcification (calcification score 100 or more). In Spearman's rank correlations, sclerostin levels significantly associated with age, intact parathyroid hormone, bone-specific alkaline phosphatase, and percent calcification. Multivariable regression showed that age, male gender, and sclerostin each significantly associated with the presence of medial vascular calcification. Receiver operating characteristic curve analysis showed that sclerostin (AUC 0.68) predicted vascular calcification. Vascular sclerostin mRNA and protein expressions were low or absent, and did not differ between calcified and non-calcified vessels, suggesting that the vasculature is not a major contributor to circulating levels. Thus, high serum sclerostin levels associate with the extent of vascular calcification as evaluated both by coronary artery CT and scoring of epigastric artery calcification. Among circulating biomarkers of mineral bone disorder, only sclerostin predicted vascular calcification.
Sundeep Khosla - One of the best experts on this subject based on the ideXlab platform.
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hormonal and systemic regulation of sclerostin
Bone, 2017Co-Authors: Matthew T Drake, Sundeep KhoslaAbstract:Abstract The Wnt/β-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non-hormonal/systemic factors which have been studied for their impact on sclerostin regulation.
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effects of age on bone mrna levels of sclerostin and other genes relevant to bone metabolism in humans
Bone, 2014Co-Authors: Matthew M Roforth, Matthew T Drake, Louise K Mccready, James M Peterson, Koji Fujita, Ulrike Mcgregor, Salman Kirmani, David G Monroe, Sundeep KhoslaAbstract:article i nfo Althoughagingisassociatedwithadeclineinboneformationinhumans,themolecularpathwayscontributingto this decline remain unclear. Several previous clinical studies have shown that circulating sclerostin levels in- crease with age, raising the possibility that increased production of sclerostin by osteocytes leads to the age- related impairment in bone formation. Thus, in the present study, we examined circulating sclerostin levels as well as bone mRNA levels of sclerostin using quantitative polymerase chain reaction (QPCR) analyses in needle bone biopsies from young (mean age, 30.0years) versus old (mean age, 72.9years) women. In addition, we an- alyzedtheexpression of genes inanumberofpathwaysknown to bealteredwith skeletal aging,basedlargelyon studies in mice. While serum sclerostin levels were 46% higher (p b 0.01) in the old as compared to the young women, bone sclerostin mRNA levelswere no differentbetween the two groups(p=0.845).However, genes re- latedtonotchsignalingweresignificantlyupregulated(p=0.003whenanalyzedasagroup)inthebiopsiesfrom the old women. In an additional analysis of 118 genes including those from genome-wide association studies re- latedtobonedensityand/or fracture,BMP/TGFβfamilygenes,selectedgrowth factorsandnuclear receptors,and Wnt/Wnt-related genes,we found that mRNA levelsof theWnt inhibitor,SFRP1,weresignificantlyincreased (by 1.6-fold, p = 0.0004, false discovery rate (q) = 0.04) in the biopsies from the old as compared to the young
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relation of age gender and bone mass to circulating sclerostin levels in women and men
Journal of Bone and Mineral Research, 2011Co-Authors: Ulrike I Modder, Kelley A Hoey, Shreyasee Amin, Louise K Mccready, Sara J Achenbach, Lawrence B Riggs, Joseph L Melton, Sundeep KhoslaAbstract:Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population-based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean ± SEM) were significantly higher in men than women (33.3 ± 1.0 pmol/L versus 23.7 ± 0.6 pmol/L, p < .001). In pre- and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4- and 4.6-fold in the women and men, respectively. Moreover, for a given total-body bone mineral content, elderly subjects (age ≥ 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age-related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age-related impairment in bone formation. © 2011 American Society for Bone and Mineral Research.
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regulation of circulating sclerostin levels by sex steroids in women and in men
Journal of Bone and Mineral Research, 2011Co-Authors: Ulrike I Modder, Kelley A Hoey, Louise K Mccready, Lawrence B Riggs, Jackie A Clowes, James M Peterson, Merry Jo Oursler, Sundeep KhoslaAbstract:Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels. E treatment of postmenopausal women (n = 17) for 4 weeks led to a 27% decrease in serum sclerostin levels [versus +1% in controls (n = 18), p < .001]. Similarly, in 59 elderly men, we eliminated endogenous E and T production and studied them under conditions of physiologic T and E replacement, and then following withdrawal of T or E, we found that E, but not T, prevented increases in sclerostin levels following induction of sex steroid deficiency. In both sexes, changes in sclerostin levels correlated with changes in bone-resorption, but not bone-formation, markers (r = 0.62, p < .001, and r = 0.33, p = .009, for correlations with changes in serum C-terminal telopeptide of type 1 collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E but not by T. Moreover, consistent with recent data indicating important effects of Wnts on osteoclastic cells, our findings suggest that in humans, changes in sclerostin production may contribute to effects of E on bone resorption. © 2011 American Society for Bone and Mineral Research.
Socrates E Papapoulos - One of the best experts on this subject based on the ideXlab platform.
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Circulating Sclerostin Levels Are Decreased in Patients with Endogenous Hypercortisolism and Increase after Treatment
2016Co-Authors: Antoon Van Lierop, A. W. Van Der Eerden, N. A. T. Hamdy, A. R. Hermus, Den M. Heijer, Socrates E PapapoulosAbstract:Context: Increasedbonefragility is a frequent complicationofhypercortisolismduepredominantly to suppression of bone formation. Sclerostin is an osteocyte-produced negative regulator of bone formation, which is up-regulated by glucocorticoids in mice. Objective: Our objective was to assess the effect of endogenous hypercortisolism on circulating sclerostin and bone turnover in humans. Design: We measured sclerostin, -C-terminal telopeptide, amino-terminal propeptide of type 1 procollagen, and fibroblast growth factor 23 in blood samples of 21 patients with endogenous hypercortisolism and 21 age- and gender-matched controls. In 12 patients, measurements were repeated at various time intervals after successful surgical treatment (transsphenoidal surgery or adrenalectomy). Results: Plasma sclerostin levels were significantly decreased in patients compared with controls (112 49 vs. 207 48 pg/ml, P 0.001). In the 12 patients who were evaluated after surgical treatment, sclerostin levels increased from 121.4 46.5 to 175.8 78.5 pg/ml (P 0.003). These changes in plasma sclerostin levelswere accompaniedby significant increases in levels of fibroblast growth factor 23 (from 44.2 12.2 to 84.0 58.8 pg/ml, P 0.017) and of the bone turnove
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association of circulating sclerostin with bone mineral mass microstructure and turnover biochemical markers in healthy elderly men and women
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Claire Durosier, Socrates E Papapoulos, Antoon Van Lierop, Serge Ferrari, Thierry Chevalley, Rene RizzoliAbstract:Context: Sclerostin inhibits bone formation and is involved in the bone response to mechanical loading, but the role and significance of circulating sclerostin are poorly understood. Objective: We assessed the association between serum sclerostin and calcitropic hormones, bone turnover marker levels, bone mineral content/density, and microstructure using 3 different immunoassays. Design, Setting, and Participants: In a cross-sectional study, serum sclerostin was measured in a cohort of 187 healthy subjects (98 women; 89 men) aged 65 ± 1 (±SD) years. Results: Overall, mean sclerostin (95% confidence interval) was 37.3 (18.0–69.2) ng/L, 1165.8 (464.0–2296.4) ng/L, and 513.5 (250.7–950.9) ng/L with assays I, II, and III, respectively. Serum sclerostin was higher in men with assays II and III. In all 3 assays, sclerostin and PTH were inversely correlated, only after adjustment for whole-body bone mineral content (WB-BMC). After adjustment for sex and WB-BMC, the bone turnover markers amino-terminal propeptide...
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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 and the regulation of bone formation effects in hip osteoarthritis and femoral neck fracture
Journal of Bone and Mineral Research, 2010Co-Authors: J Power, Rutger L Van Bezooijen, Socrates E Papapoulos, Clemens W G M Lowik, Kenneth E S Poole, Michael Doube, A M Caballeroalias, Jonathan Reeve, N LoveridgeAbstract:Remodeling imbalance in the elderly femoral neck can result in thin cortices and porosity predisposing to hip fracture. Hip osteoarthritis protects against intracapsular hip fracture. By secreting sclerostin, osteocytes may inhibit Wnt signaling and reduce bone formation by osteoblasts. We hypothesised that differences in osteocytic sclerostin expression might account for differences in osteonal bone-formation activity between controls and subjects with hip fracture or hip osteoarthritis. Using specific antibody staining, we determined the osteocytic expression of sclerostin within osteons of the femoral neck cortex in bone removed from subjects undergoing surgery for hip osteoarthritis (hOA: 5 males, 5 females, 49 to 92 years of age) or hip fracture fixation (FNF: 5 males, 5 females, 73 to 87 years of age) and controls (C: 5 males, 6 females, 61 to 90 years of age). Sclerostin expression and distances of each osteocyte to the canal surface and cement line were assessed for all osteonal osteocytes in 636 unremodeled osteons chosen from fields ( approximately 0.5 mm in diameter) with at least one canal staining for alkaline phosphatase (ALP), a marker of bone formation. In adjacent sections, ALP staining was used to classify basic multicellular unit (BMUs) as quiescent or actively forming bone (ALP(+)). The areal densities of scl(-) and scl(+) osteocytes (number of cells per unit area) in the BMU were inversely correlated and were strong determinants of ALP status in the BMU. In controls and hip fracture patients only, sclerostin-negative osteocytes were closer to osteonal surfaces than positively stained cells. Osteon maturity (progress to closure) was strongly associated with the proportion of osteonal osteocytes expressing sclerostin, and sclerostin expression was the chief determinant of ALP status. hOA patients had 18% fewer osteocytes per unit bone area than controls, fewer osteocytes expressed sclerostin on average than in controls, but wide variation was seen between subjects. Thus, in most hOA patients, there was increased osteonal ALP staining and reduced sclerostin staining of osteocytes. In FNF patients, newly forming osteons were similar in this respect to hOA osteons, but with closure, there was a much sharper reduction in ALP staining that was only partly accounted for by the increased proportions of osteonal osteocytes staining positive for sclerostin. There was no evidence for a greater effect on ALP expression by osteocytes near the osteonal canal. In line with data from blocking antibody experiments, osteonal sclerostin appears to be a strong determinant of whether osteoblasts actively produce bone. In hOA, reduced sclerostin expression likely mediates increased osteoblastic activity in the intracapsular cortex. In FNF, full osteonal closure is postponed, with increased porosity, in part because the proportion of osteocytes expressing sclerostin increases sharply with osteonal maturation.
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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.
Christiane Drechsler - One of the best experts on this subject based on the ideXlab platform.
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mendelian randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures
Journal of Bone and Mineral Research, 2019Co-Authors: Jie Zheng, Vincent Brandenburg, Christiane Drechsler, Christoph Wanner, Winfried Maerz, Ingrid Gergei, Marcus E Kleber, Sjur ReppeAbstract:In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (β = 0.20, p = 4.6 × 10-49 ) and GALNT1 (β = 0.11 per G allele, p = 4.4 × 10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (β = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (β = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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mendelian randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures
bioRxiv, 2019Co-Authors: Jie Zheng, Vincent Brandenburg, Christiane Drechsler, Christoph Wanner, Winfried Maerz, Ingrid Gergei, Marcus E Kleber, Sjur ReppeAbstract:ABSTRACT In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6×10−49), and GALNT1 (β=0.11 per G allele, P=4.4×10−11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= −0.12, 95%CI= −0.20 to −0.05) and eBMD (β= −0.12, 95%CI= −0.14 to −0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.
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genome wide mapping identifies beta 1 4 n acetyl galactosaminyl transferase as a novel determinant of sclerostin levels and bone mineral density
bioRxiv, 2018Co-Authors: Jie Zheng, Vincent Brandenburg, Christiane Drechsler, Christoph Wanner, Winfried Maerz, Ingrid Gergei, Marcus E Kleber, Sjur Reppe, Kaare M Gautvik, Carolina MedinagomezAbstract:ABSTRACT In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Sclerostin is also present at detectable concentrations within the circulation. Our genome wide association study (GWAS) meta-analysis of 10,584 European-descent individuals identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD) change in sclerostin per A allele β=0.20, P=4.6x10-49), and GALNT1 (β=0.11 per G allele, P=4.4x10-11), of which the former is a known locus for BMD estimated by heel ultrasound (eBMD). Common variants across the genome explained 16% of the phenotypic variation of serum sclerostin. Mendelian randomization revealed an inverse causal relationship between serum sclerostin and femoral neck BMD and eBMD, and a positive relationship with fracture risk. Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower BMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Renal and cortical bone tissue, and osteoblast cultures, were found to express high levels of B4GALNT3, an N-acetylgalactosaminyltransferase which adds a terminal LacdiNAc disaccharide to target glycocoproteins. Together, these findings raise the possibility that sclerostin is a substrate for B4GALNT3, such that its modification leads to higher levels, possibly through greater stability. GALNT1, an enzyme causing mucin-type O-linked glycosylation, may act in a similar capacity. We conclude that genetic variation in glycosylation enzymes represents a novel determinant of BMD and fracture risk, acting via alterations in levels of circulating sclerostin.
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high levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients results from the necosad study
Nephrology Dialysis Transplantation, 2015Co-Authors: Nikolaus Marx, Christiane Drechsler, Markus Ketteler, Pieter Evenepoel, Marc G Vervloet, Christoph Wanner, J Floege, Friedo W Dekker, Vincent BrandenburgAbstract:Background. Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover, and it plays a role in cardiovascular calcification processes. Previous findings indicate that sclerostin regulation is disturbed in chronic kidney disease (CKD). The aim of this study was to assess the association of circulating sclerostin levels with mortality in dialysis patients. Methods. From a prospective cohort study of incident dialysis patients in the Netherlands, all patients with measured circulating sclerostin at 3 months after the start of dialysis (baseline) were included in the present analysis: n = 673, age 63 ± 14 years, mean serum sclerostin (ELISA) 1.24 ± 0.57 ng/mL. By Cox regression analyses, we assessed the association of sclerostin levels with cardiovascular and non-cardiovascular mortality both in the short (18 months) and long term (4-year follow-up). Results. Serum sclerostin levels in the entire cohort correlated with intact parathyroid hormone levels (r = −0.25, P < 0.001), age (r = 0.16, P < 0.001) and serum alkaline phosphatase (r = −0.13, P = 0.001). After adjustment for various clinical and biochemical parameters, patients in the highest sclerostin tertile had a significantly lower risk of cardiovascular death [hazard ratio 0.29, 95% confidence interval (CI) 0.13–0.62] and for all-cause mortality (0.39, 95% CI 0.22–0.68) within 18 months compared with patients of the lowest tertile. The association of sclerostin levels with outcome was less pronounced for long-term cardiovascular mortality and absent for noncardiovascular mortality. Conclusions. High levels of serum sclerostin are associated with lower short-term cardiovascular mortality in dialysis patients. The exact mechanisms of this association, e.g. how sclerostin influences or reflects uraemic vascular calcification, need to be investigated in further studies.
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relationship between sclerostin and cardiovascular calcification in hemodialysis patients a cross sectional study
BMC Nephrology, 2013Co-Authors: Vincent Brandenburg, Rafael Kramann, Ralf Koos, Thilo Kruger, Leon J Schurgers, Georg Muhlenbruch, Sinah Hubner, Ulrich Gladziwa, Christiane Drechsler, Markus KettelerAbstract:Background: Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. Methods: We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 ± 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR). Results: CAC (Agatston score > 100) and any AVC were present in 65% and in 40% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 ± 0.81 vs 0.76 ± 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 ± 0.84 vs 1.35 ± 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n= 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves. Conclusion: We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.
Manuel Munoztorres - One of the best experts on this subject based on the ideXlab platform.
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atherosclerotic disease in type 2 diabetes is associated with an increase in sclerostin levels
Diabetes Care, 2013Co-Authors: Sonia Moralessantana, Antonia Garciamartin, Pedro Rozasmoreno, Rebeca Reyesgarcia, Beatriz Garciafontana, Jose A Garciasalcedo, Manuel MunoztorresAbstract:OBJECTIVE Wnt/β-catenin signaling is related to the pathogenesis of several diseases. Sclerostin is an inhibitor of Wnt/β-catenin signaling. However, there are few data regarding the sclerostin levels and vascular disease. Our aim was to examine the relationship between serum sclerostin and atherosclerotic disease (AD) in type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We performed a cross-sectional study including 78 T2DM patients (45.3% females, mean age 59 ± 5.7 years; 54.7% males, 57.4 ± 6.7 years). RESULTS Serum sclerostin concentrations of T2DM patients in the AD group were significantly higher than in the non-AD group ( P = 0.006). For each increase of 1 pmol/L in sclerostin level, there was a 4% increase of the risk of AD in T2DM patients. A concentration of ≥42.3 pmol/L showed a sensitivity of 69% and a specificity of 54.8% to detect an increased risk of AD. In males, sclerostin levels were higher in those with AD ( P = 0.04), abnormal intima-media thickness (IMT) ( P = 0.004), carotid plaques ( P P P = 0.03) and aortic calcifications ( P = 0.004). Homocysteine (β = 0.319 [95% CI 0.561–2.586], P = 0.003) and IMT (β = 0.330 [14.237–67.693], P = 0.003) were positive correlated with sclerostin. CONCLUSIONS Circulating sclerostin is increased in T2DM patients with atherosclerotic lesions. Although the sample size of our study was small, these data suggest that sclerostin levels could be a major modulator of Wnt signaling in AD with implications in T2DM patients.
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circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Antonia Garciamartin, Pedro Rozasmoreno, Rebeca Reyesgarcia, Sonia Moralessantana, Beatriz Garciafontana, Jose A Garciasalcedo, Manuel MunoztorresAbstract:Context: Diabetes mellitus is a risk factor for osteoporotic fractures. Sclerostin is an inhibitor of bone formation. However, there are no data about sclerostin levels in type 2 diabetes mellitus (T2DM). Objectives: The aims were to evaluate serum sclerostin in T2DM patients and to analyze its relationship with bone metabolism. Design, Setting, and Patients: This was a cross-sectional study. We compared serum sclerostin in the T2DM group (n = 74) and control group (n = 50), and we analyzed its relationship with calciotropic hormones, bone turnover markers, bone mineral density (BMD), and morphometric vertebral fractures. Results: Sclerostin levels were significantly higher in T2DM patients than control subjects (P < 0.001) and in T2DM males than in T2DM females (P < 0.001). Serum sclerostin was positively correlated with age in males T2DM (P = 0.031). In linear regression analysis, gender, study group, and age were predictive of sclerostin levels (P < 0.05). Sclerostin concentrations were positively asso...