University of Oulu

Sofia Movérare-Skrtic, Jakob Voelkl, Karin H. Nilsson, Maria Nethander, Trang Thi Doan Luong, Ioana Alesutan, Lei Li, Jianyao Wu, Karin Horkeby, Marie K. Lagerquist, Antti Koskela, Juha Tuukkanen, Jon H. Tobias, Ulf H. Lerner, Petra Henning, Claes Ohlsson, B4GALNT3 regulates glycosylation of sclerostin and bone mass, eBioMedicine, Volume 91, 2023, 104546, ISSN 2352-3964,

B4GALNT3 regulates glycosylation of sclerostin and bone mass

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Author: Movérare-Skrtic, Sofia1; Voelkl, Jakob2,3,4; Nilsson, Karin H.1;
Organizations: 1Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
2Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
3Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
4DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
5Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
6Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
7Musculoskeletal Research Unit, Translational Health Sciences, and Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
8Region Västra Götaland, Department of Drug Treatment, Sahlgrenska University Hospital, Gothenburg, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.7 MB)
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Language: English
Published: Elsevier, 2023
Publish Date: 2023-09-04


Background: Global sclerostin inhibition reduces fracture risk efficiently but has been associated with cardiovascular side effects. The strongest genetic signal for circulating sclerostin is in the B4GALNT3 gene region, but the causal gene is unknown. B4GALNT3 expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3 that transfers N-acetylgalactosamine onto N-acetylglucosaminebeta-benzyl on protein epitopes (LDN-glycosylation).

Methods: To determine if B4GALNT3 is the causal gene, B4galnt3−/− mice were developed and serum levels of total sclerostin and LDN-glycosylated sclerostin were analysed and mechanistic studies were performed in osteoblast-like cells. Mendelian randomization was used to determine causal associations.

Findings: B4galnt3−/− mice had higher circulating sclerostin levels, establishing B4GALNT3 as a causal gene for circulating sclerostin levels, and lower bone mass. However, serum levels of LDN-glycosylated sclerostin were lower in B4galnt3−/− mice. B4galnt3 and Sost were co-expressed in osteoblast-lineage cells. Overexpression of B4GALNT3 increased while silencing of B4GALNT3 decreased the levels of LDN-glycosylated sclerostin in osteoblast-like cells. Mendelian randomization demonstrated that higher circulating sclerostin levels, genetically predicted by variants in the B4GALNT3 gene, were causally associated with lower BMD and higher risk of fractures but not with higher risk of myocardial infarction or stroke. Glucocorticoid treatment reduced B4galnt3−/− expression in bone and increased circulating sclerostin levels and this may contribute to the observed glucocorticoid-induced bone loss.

Interpretation: B4GALNT3 is a key factor for bone physiology via regulation of LDN-glycosylation of sclerostin. We propose that B4GALNT3-mediated LDN-glycosylation of sclerostin may be a bone-specific osteoporosis target, separating the anti-fracture effect of global sclerostin inhibition, from indicated cardiovascular side effects.

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Series: EBioMedicine
ISSN: 2352-3964
ISSN-E: 2352-3964
ISSN-L: 2352-3964
Volume: 91
Article number: 104546
DOI: 10.1016/j.ebiom.2023.104546
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study was supported by the Swedish Research Council (2016-01001, 2018-02921, 2020-01392, 2022-01156), the Swedish Foundation of Strategic Research (FFL15-0188), the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement in Gothenburg (ALFGBG-720331, ALFGBG-965235, ALFGBG-721621, ALFGBG-965362), the IngaBritt and Arne Lundberg Foundation (LU2017-0081, LU2021-0096), the Knut and Alice Wallenberg Foundation (KAW 2015.0317), and the Novo Nordisk Foundation (NNF15OC0015080, NNF190C0055250, NNF20OC0063954). The MEGASTROKE project received funding from sources specified at (Supplemental Table S7).
Copyright information: © 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (