B4GALNT3 调节骨钙素的糖基化和骨量。
B4GALNT3 regulates glycosylation of sclerostin and bone mass.
机构信息
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
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.
出版信息
EBioMedicine. 2023 May;91:104546. doi: 10.1016/j.ebiom.2023.104546. Epub 2023 Apr 4.
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.
背景
全球抑制硬骨素可有效降低骨折风险，但与心血管副作用相关。循环硬骨素最强的遗传信号位于 B4GALNT3 基因区域，但因果基因未知。B4GALNT3 表达的酶β-1,4-N-乙酰半乳糖胺基转移酶 3 将 N-乙酰半乳糖胺转移到蛋白表位上的 N-乙酰葡萄糖胺β-苄基（LDN-糖基化）。
方法
为确定 B4GALNT3 是否为因果基因，构建了 B4galnt3 小鼠，并分析了血清总硬骨素和 LDN-糖基化硬骨素水平，并在成骨样细胞中进行了机制研究。孟德尔随机化用于确定因果关联。
结果
B4galnt3 小鼠具有更高的循环硬骨素水平，证实 B4GALNT3 是循环硬骨素水平的因果基因，并导致骨量减少。然而，B4galnt3 小鼠的血清 LDN-糖基化硬骨素水平较低。B4galnt3 和 Sost 在成骨细胞系细胞中共表达。B4GALNT3 的过表达增加，而 B4GALNT3 的沉默降低了成骨样细胞中 LDN-糖基化硬骨素的水平。孟德尔随机化表明，B4GALNT3 基因变异预测的循环硬骨素水平升高与 BMD 降低和骨折风险增加有关，但与心肌梗死或中风风险增加无关。糖皮质激素治疗降低了骨中的 B4galnt3 表达并增加了循环硬骨素水平，这可能导致观察到的糖皮质激素诱导的骨丢失。
结论
B4GALNT3 通过调节硬骨素的 LDN-糖基化是骨生理学的关键因素。我们提出，B4GALNT3 介导的硬骨素的 LDN-糖基化可能是一种骨特异性骨质疏松靶点，将全球硬骨素抑制的抗骨折作用与明确的心血管副作用分开。
资金
在致谢中列出。
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