B4GALNT3 regulates glycosylation of sclerostin and bone massResearch in context
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
Affiliations
Sofia Movérare-Skrtic
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Corresponding author. Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden.
Jakob Voelkl
Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
Karin H. Nilsson
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Maria Nethander
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Trang Thi Doan Luong
Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
Ioana Alesutan
Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
Lei Li
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Jianyao Wu
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Karin Horkeby
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Marie K. Lagerquist
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Antti Koskela
Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
Juha Tuukkanen
Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
Jon H. Tobias
Musculoskeletal Research Unit, Translational Health Sciences, and Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
Ulf H. Lerner
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Petra Henning
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Claes Ohlsson
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Region Västra Götaland, Department of Drug Treatment, Sahlgrenska University Hospital, Gothenburg, Sweden
Summary: 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. Funding: Found in acknowledgements.
