Loss of the glycosyltransferase Galnt11 affects vitamin D homeostasis and bone composition.

Autor:	Tian E; Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Rothermel C; Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Michel Z; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., de Castro LF; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Lee J; Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Kilts T; Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Kent T; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Collins MT; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA., Ten Hagen KG; Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: Kelly.Tenhagen@nih.gov.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Apr; Vol. 300 (4), pp. 107164. Date of Electronic Publication: 2024 Mar 12.
DOI:	10.1016/j.jbc.2024.107164
Abstrakt:	O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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