TY  - JOUR
AB  - 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.
AU  - Zheng, J.*
AU  - Maerz, W.*
AU  - Gergei, I.*
AU  - Kleber, M.*
AU  - Drechsler, C.*
AU  - Wanner, C.*
AU  - Brandenburg, V.*
AU  - Reppe, S.*
AU  - Gautvik, K.M.*
AU  - Medina-Gomez, C.*
AU  - Shevroja, E.*
AU  - Gilly, A.
AU  - Park, Y.C.*
AU  - Dedoussis, G.*
AU  - Zeggini, E.
AU  - Lorentzon, M.*
AU  - Henning, P.*
AU  - Lerner, U.H.*
AU  - Nilsson, K.*
AU  - Movérare-Skrtic, S.*
AU  - Baird, D.*
AU  - Elsworth, B.L.*
AU  - Falk, L.*
AU  - Groom, A.*
AU  - Capellini, T.D.*
AU  - Grundberg, E.*
AU  - Nethander, M.*
AU  - Ohlsson, C.*
AU  - Smith, G.D.*
AU  - Tobias, J.H.*
C1  - 56270
C2  - 46951
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1824-1836
TI  - Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures.
JO  - J. Bone Min. Res.
VL  - 34
IS  - 10
PB  - Wiley
PY  - 2019
SN  - 0884-0431
ER  - 

TY  - JOUR
AB  - The X-linked WTX/AMER1 protein constitutes an important component of the β-catenin destruction complex that can both enhance and suppress canonical β-catenin signaling. Somatic mutations in WTX/AMER1 have been found in a proportion of the pediatric kidney cancer Wilms' tumor. By contrast, germline mutations cause the severe sclerosing bone dysplasia osteopathia striata congenita with cranial sclerosis (OSCS), a condition usually associated with fetal or perinatal lethality in male patients. Here we address the developmental and molecular function of WTX by generating two novel mouse alleles. We show that in addition to the previously reported skeletal abnormalities, loss of Wtx causes severe midline fusion defects including cleft palate and ectopic synostosis at the base of the skull. By contrast, deletion of the C-terminal part of the protein results in only mild developmental abnormalities permitting survival beyond birth. Adult analysis, however, revealed skeletal defects including changed skull morphology and an increased whole-body bone density, resembling a subgroup of male patients carrying a milder, survivable phenotype. Molecular analysis in vitro showed that while β-catenin fails to co-immunoprecipitate with the truncated protein, partial recruitment appears to be achieved in an indirect manner using AXIN/AXIN2 as a molecular bridge. Taken together our analysis provides a novel model for WTX-caused bone diseases and explains on the molecular level how truncation mutations in this gene may retain some of WTX-protein functions.
AU  - Comai, G.*
AU  - Boutet, A.*
AU  - Tanneberger, K.*
AU  - Massa, F.*
AU  - Rocha, A.-S.*
AU  - Charlet, A.*
AU  - Panzolini, C.*
AU  - Motamedi, F.J.*
AU  - Brommage, R.
AU  - Hans, W.
AU  - Funck-Brentano, T.*
AU  - Hrabě de Angelis, M.
AU  - Hartmann, C.*
AU  - Cohen-Solal, M.*
AU  - Behrens, J.*
AU  - Schedl, A.*
C1  - 52717
C2  - 44354
SP  - 875-887
TI  - Genetic and molecular insights into genotype-phenotype relationships in osteopathia striata with cranial sclerosis (OSCS) through the analysis of novel mouse Wtx mutant alleles.
JO  - J. Bone Min. Res.
VL  - 33
IS  - 5
PY  - 2018
SN  - 0884-0431
ER  - 

TY  - JOUR
AU  - Schmidt, J.
AU  - Casser-Bette, M.
AU  - Murray, A.B.
AU  - Closs, E.I.
AU  - Strauß, P.G.
AU  - Erfle, V.
C1  - 17171
C2  - 10286
TI  - A Three-dimensionall Cell Culture System for Testing Osteogenetic Potential and Studying Osteogenic Differentiation in Vitro.
JO  - J. Bone Min. Res.
PY  - 1988
SN  - 0884-0431
ER  -