Abstract
Bone formation is indirectly influenced by 1,25-dihydroxyvitamin D3 (1,25D3) through the stimulation of calcium uptake in the intestine and re-absorption in the kidneys. Direct effects on osteoblasts and bone formation have also been established. The vitamin D receptor (VDR) is expressed in osteoblasts and 1,25D3 modifies gene expression of various osteoblast differentiation and mineralization-related genes, such as alkaline phosphatase (ALPL), osteocalcin (BGLAP), and osteopontin (SPP1). 1,25D3 is known to stimulate mineralization of human osteoblasts in vitro, and recently it was shown that 1,25D3 induces mineralization via effects in the period preceding mineralization during the pre-mineralization period. For a full understanding of the action of 1,25D3 in osteoblasts it is important to get an integrated network view of the 1,25D3-regulated genes during osteoblast differentiation and mineralization. The current data will be presented and discussed alluding to future studies to fully delineate the 1,25D3 action in osteoblast. Describing and understanding the vitamin D regulatory networks and identifying the dominant players in these networks may help develop novel (personalized) vitamin D-based treatments. The following topics will be discussed in this overview: (1) Bone metabolism and osteoblasts, (2) Vitamin D, bone metabolism and osteoblast function, (3) Vitamin D induced transcriptional networks in the context of osteoblast differentiation and bone formation.
Highlights
Vitamin D and gene networks in human osteoblastsA full explanation for this apparent discrepancy between human and murine osteoblasts is absent
Bone formation is indirectly influenced by 1,25-dihydroxyvitamin D3 (1,25D3) through the stimulation of calcium uptake in the intestine and re-absorption in the kidneys
This study showed functionality of 1α-hydroxylation in human osteoblast differentiation. 25D3 induced expression of CYP24, osteocalcin and stimulated ALPL activity and mineralization, which was blocked by inhibition of 1α-hydroxylase by ketoconazole
Summary
A full explanation for this apparent discrepancy between human and murine osteoblasts is absent Both the extracellular milieu (i.e., presence/absence of growth factors, cytokines and other signaling molecules) and the intracellular milieu (e.g., the insulin-like growth factor binding protein-6 that can bind to the VDR and inhibit 1,25D3 induction of ALPL activity) of the cell is important for the eventual effect of 1,25D3 (Cui et al, 2011). 1,25D3 plays an important role in maintaining bone health either via controlling calcium and phosphate homeostasis or via direct effects on osteoblasts This latter is supported by the direct effects of 1,25D3 on osteoblast differentiation, expression and activity of bone formation related proteins and enzymes, and mineralization. Stable expression of BMP2K in mouse osteoprogenitor cells decreased ALPL activity and osteocalcin mRNA levels This suggests that 1,25D3 induced expression of miR1228 may affect osteoblast differentiation via down-regulation of BMP2K.
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