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

Meng, Fangang; Bertucci, C.P.; Gao, Yuan; Li, Jing; Luu, Simon; LeBoff, Meryl S.; Glowacki, Julie; Zhou, Shuanhu

doi:10.1016/j.jsbmb.2020.105587

Cited by 9 publications

(13 citation statements)

References 69 publications

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“…Excess FGF23 has both indirect effects on bone and cartilage mineralization mediated by the reductions in serum phosphate and 1,25(OH)2D (31,32) , as well as possible direct effects due to FGF23 activation of FGFRs in osteoblasts (33,34) . We observed substantial improvement in bone abnormalities after only 4 weeks of treatment as well as alteration in gene expression profiles in bone.…”

Section: Discussionmentioning

confidence: 99%

Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities inHypmice

Xiao

Liu

et al. 2020

Preprint

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Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that binds to binary FGFR/α-Klotho receptor complexes in the kidney tubules to inhibit phosphate reabsorption and 1,25(OH)2D production. Excess FGF23 causes X-linked hypophosphatemia (XLH) and tumor induced osteomalacia (TIO). Recently, Burosumab, an FGF23 blocking antibody, was approved for treating these hypophosphatemic disorders. A small molecule inhibitor that specifically binds to FGF23 to prevent activation of FGFR/α-Klotho complexes has potential advantages over a systemically administered FGF23 blocking antibody. We previously identified the small molecule ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a therapeutic lead FGF23 antagonist. Additional structure-activity studies developed a series of ZINC13407541 analogues with enhanced drug-like properties. In this study, we tested in a pre-clinical Hyp mouse homologue of XLH a direct connect analogue (8n) [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] that exhibited the greatest stability in microsomal assays, and 13a [(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] that exhibited increased in vitro potency. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and significantly increased serum phosphate and 1,25(OH)2D concentrations in Hyp mice. Long-term parenteral treatment with 8n or 13a also enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate in Hyp mice. The more potent 13a compound showed greater therapeutic efficacy in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat FGF23-mediated disorders.

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Section: Discussionmentioning

confidence: 99%

Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities inHypmice

Xiao

Liu

et al. 2020

Preprint

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“…A recent study of this team [86] documented that 1,25D markedly stimulated the expression of FGF-23, and the mature OB marker, BGLAP, in primary OBs derived from CKD patients. However, recombinant human FGF-23 countered VD-stimulated OBs differentiation of human bone marrow stromal cells (hMSCs) by reducing VDR and CYP27B1 expression as well as inhibiting 1,25D biosynthesis and signaling through bone morphogenic protein-7 (BMP-7) [93]. 1,25D in very high concentration (100 nM), which far exceeds the concentrations achieved in dialysis patients receiving high doses of calcitriol, improved in vitro OBs mineralization.…”

Section: Role Of Vitamin K and Vitamin D In Bone Remodeling In Ckdmentioning

confidence: 99%

Vitamin K and D Supplementation and Bone Health in Chronic Kidney Disease—Apart or Together?

2021

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Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately.

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“…FGF23 directly suppressed the activity of 1-α hydroxylase and increased the activity of 25-hydroxyvitamin D3-24-hydroxylase [109,110]. The decrease of vitamin D and the increase of FGF23 interfered with the osteogenic differentiation of bone marrow MSCs in CKD patients [111][112][113]. Therefore, the correction of vitamin D deficiency is critical to the treatment of vascular calcification, and the synergy of vitamin D and MSCs should be considered in the treatment of vascular calcification.…”

Section: Possible Therapeutic Roles Of Vitamin D In Mscs and Vascularmentioning

confidence: 99%

“…In vitro, rhFGF23 counters 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. Thus, the dysregulated vitamin D metabolism in hMSCs may contribute to impaired osteoblastogenesis and altered mineral metabolism in CKD subjects [113]. From the in vitro study initiated by Wang et al, the culture medium of MSCs decreased the calcium deposition in the VSMC because of the decreased expression of TNF-α, IL-1β, and IL-6 ( Figure 2) [134].…”

Section: The Role Of Vitamin D and Mscs/pericytes In Vascular Calcifimentioning

confidence: 99%

Section: The Role Of Vitamin D and Mscs/pericytes In Vascular Calcifimentioning

confidence: 99%

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The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification

Hou

Zheng

et al. 2020

IJMS

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Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification.

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

Cited by 9 publications

References 69 publications

Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities inHypmice

Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities inHypmice

Vitamin K and D Supplementation and Bone Health in Chronic Kidney Disease—Apart or Together?

The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification

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