Fibroblast growth factor 23 counters vitamin D metabolism and action in human mesenchymal stem cells

Autor: Shuanhu Zhou, Jing Li, Julie Glowacki, Fangang Meng, Yuan Gao, Simon Luu, Meryl S. LeBoff, Christopher Bertucci
Rok vydání: 2019
Předmět:
0301 basic medicine
Fibroblast growth factor 23
Male
endocrine system
medicine.medical_specialty
Endocrinology
Diabetes and Metabolism
Bone Morphogenetic Protein 7
Clinical Biochemistry
Kidney
Biochemistry
Calcitriol receptor
03 medical and health sciences
Paracrine signalling
0302 clinical medicine
Endocrinology
Osteogenesis
Internal medicine
medicine
Humans
Receptor
Fibroblast Growth Factor
Type 1
Renal Insufficiency
Chronic
Vitamin D
Autocrine signalling
Molecular Biology
Aged
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Aged
80 and over
Osteoblasts
Chemistry
Fibroblast growth factor receptor 1
Mesenchymal stem cell
Gene Expression Regulation
Developmental
Osteoblast
Cell Differentiation
Mesenchymal Stem Cells
Cell Biology
Middle Aged
equipment and supplies
Bone morphogenetic protein 7
Fibroblast Growth Factors
Fibroblast Growth Factor-23
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Molecular Medicine
Receptors
Calcitriol
Female
Glomerular Filtration Rate
Zdroj: The Journal of steroid biochemistry and molecular biology. 199
ISSN: 1879-1220
Popis: Chronic kidney disease (CKD) is associated with elevated circulating fibroblast growth factor 23 (FGF23), impaired renal biosynthesis of 1α,25-dihydroxyvitamin D (1α,25(OH)2D), low bone mass, and increased fracture risk. Our previous data with human mesenchymal stem cells (hMSCs) indicated that vitamin D metabolism in hMSCs is regulated as it is in the kidney and promotes osteoblastogenesis in an autocrine/paracrine manner. In this study, we tested the hypothesis that FGF23 inhibits vitamin D metabolism and action in hMSCs. hMSCs were isolated from discarded marrow during hip arthroplasty, including two subjects receiving hemodialysis and a series of 20 subjects (aged 49-83 years) with estimated glomerular filtration rate (eGFR) data. The direct in vitro effects of rhFGF23 on hMSCs were analyzed by RT-PCR, Western immunoblot, and biochemical assays. Ex vivo analyses showed positive correlations for both secreted and membrane-bound αKlotho gene expression in hMSCs with eGFR of the subjects from whom hMSCs were isolated. There was downregulated constitutive expression of αKlotho, but not FGFR1 in hMSCs obtained from two hemodialysis subjects. In vitro, rhFGF23 countered vitamin D-stimulated osteoblast differentiation of hMSCs by reducing the vitamin D receptor, CYP27B1/1α-hydroxylase, biosynthesis of 1α,25(OH)2D3, and signaling through BMP-7. These data demonstrate that dysregulated vitamin D metabolism in hMSCs may contribute to impaired osteoblastogenesis and altered bone and mineral metabolism in CKD subjects due to elevated FGF23. This supports the importance of intracellular vitamin D metabolism in autocrine/paracrine regulation of osteoblast differentiation in hMSCs.
Databáze: OpenAIRE
Externí odkaz: