1ɑ,25‐Dihydroxyvitamin D₃ promotes osteogenesis by down‐regulating FGF23 in diabetic mice

Abstract

1ɑ,25‐dihydroxyvitamin D3 (1,25D) and fibroblast growth factor 23 (FGF23) play important roles in bone metabolism through mutual regulation. However, the underlying mechanism between 1,25D and FGF23 in diabetes‐induced bone metabolism disorders has not yet been elucidated. In this study, we investigated the effect of 1,25D on FGF23 under diabetic condition both in vitro and in vivo. The results showed that 1,25D down‐regulated the expression of FGF23 in osteoblast significantly though a dose‐dependent manner in vitro within high glucose environment. Western blot and immunofluorescence analysis indicated that 1,25D activated PI3K/Akt signalling through binding to vitamin D receptor (VDR), which inhibited the phosphorylation of the transcription factor Forkhead Box O1 (FOXO1). Decreased phosphorylation of FOXO1 down‐regulated the expression Dickkopf‐1 (DKK1), a well‐known inhibitor of Wnt signalling. In addition, we observed that 1,25D remarkably ameliorated osteogenic phenotypic markers such as Ocn and Runx2 and rescued diabetes‐induced bone loss in vivo. Our results suggested that 1,25D could promote osteogenesis though down‐regulating FOXO1/FGF23 in diabetes.

Integration of metabolomics and transcriptomics provides insights into enhanced osteogenesis in Ano5Cys360Tyr knock-in mouse model

“…Meaningfully, qRT-PCR showed that Cyp27b1 was significantly elevated in the kidneys of Ano5 KI/KI mice and a three-fold increase in Cyp27b1 mRNA accumulation was also observed in Ano5 Cys360Tyr mCOBs after 14 days of osteoblast differentiation, but not at day 0 (Figures 7F, G). Some studies have reported that calcitriol and Cyp27b1 cooperatively regulate OCN during osteogenic differentiation (43,44). Consistently, the protein levels of OCN, the most abundant non-collagenous bone matrix protein that is specifically synthesized by osteoblasts, was elevated in differentiated Ano5 KI/KI mCOBs (Figure 7H).…”

“…It is worth noting that calcitriol is involved in calcium reabsorption and mineral deposition by activating calcium channels so as to play a vital role in bone regeneration. Calcitriol can stimulate the absorption of calcium and phosphate in the small intestine, leading to generation of optimal circumstances for matrix mineralization (43,(50)(51)(52). More and more scholars have recommended adequate 1,25(OH) 2 D 3 uptake to prevent osteoporosis, wherein its anti-aging mechanism depends on promoting matrix mineralization and preventing bone resorption (53).…”

“…Based on the higher ratio of OPG/RANKL and impaired osteoclastogenesis in Ano5 KI/KI mice compared to wild type individuals, it is reasonable to speculate that increased calcitriol is crucial for bone turnover underlying GDD. In order to explore the mechanisms contributing to excessive production of calcitriol caused by the Ano5 Cys360Tyr mutation, we detected the expression levels of fibroblast growth factor 23 (Fgf23) that is primarily secreted by osteoblasts and osteocytes and regulates phosphate homeostasis and calcitriol metabolism (43), while result showed both its expression in mCOB and serum FGF23 level were comparable between Ano5 +/+ and Ano5 KI/KI group (Figure S4). In addition to FGF23, elevated serum phosphate may be attributed to abnormal metabolism of calcitriol and parathyroid hormone, and the specific mechanism remains to be further explored.…”

“…Apart from osteogenic differentiation, calcitriol has a crucial impact on cellular growth. Many lines of evidence have indicated that 1,25(OH) 2 D 3 could contribute to promoting proliferation of bone ancestor cells, such as stem cells from the apical papilla and human bone marrow mesenchymal stem cells (43,56). Additionally, ANO5 is known to participate in proliferation of myoblasts and some cancer cells (57).…”

Vitexin Regulates Angiogenesis and Osteogenesis in Ovariectomy-Induced Osteoporosis of Rats via the VDR/PI3K/AKT/eNOS Signaling Pathway

“…Zhang and Zanello reported that 1,25D in a dose-and time-dependent manner activates the PI3K/AKT signal by binding to VDR . To verify hypothesis that a PI3K/AKT pathway is involved in VDR anti-apoptotic functions and pretreated the cells with the PI3K inhibitor, and 1a, 25-D stimulated increases in PI3K activity were blocked by LY294002, thus confirming 1,25D binding to VDR against apoptosis through PI3K activation. , The PI3K/AKT/eNOS pathway may act as a positive regulator of endothelial NO synthase in endothelial cells and play a key role in the process of endothelial cell survival, mobilization, migration, and homing, and eNOS is a main mediator of angiogenesis. The pro-angiogenesis effect of eNOS is mediated by enhancing the expression of vascular essential factors such as NO and VEGF1–2.…”