B4galnt3, also known as β1,4 -N -acetylgalactosaminyltransferase 3, is an enzyme that transfers N -acetylgalactosamine onto N -acetylglucosamineβ -benzyl on protein epitopes (LDN -glycosylation). This glycosylation process is involved in various biological pathways and is of great biological importance. Genetic models, such as knockout mice, have been crucial in studying its functions [1,2].

B4galnt3-/-mice had higher circulating sclerostin levels but lower bone mass, establishing B4galnt3 as a causal gene for circulating sclerostin levels. Also, serum levels of LDN -glycosylated sclerostin were lower in these knockout mice. In osteoblast -like cells, overexpression of B4galnt3 increased while silencing decreased the levels of LDN -glycosylated sclerostin. Mendelian randomization showed that higher circulating sclerostin levels, genetically predicted by B4galnt3 variants, were associated with lower bone mineral density (BMD) and higher fracture risk, but not with myocardial infarction or stroke risk. Glucocorticoid treatment reduced B4galnt3 expression in bone and increased circulating sclerostin levels, potentially contributing to glucocorticoid -induced bone loss [1].

In conclusion, B4galnt3 is a key factor in bone physiology through the regulation of LDN -glycosylation of sclerostin. The study of B4galnt3-/-mice has provided valuable insights into the role of B4galnt3 in bone -related diseases, suggesting that B4GALNT3 -mediated LDN -glycosylation of sclerostin could be a bone -specific osteoporosis target, potentially separating the anti -fracture effect of global sclerostin inhibition from its cardiovascular side effects [1].