The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders

Kinoshita, Saori; Kawai, Masanobu

doi:10.1016/bs.vh.2016.02.001

Cited by 19 publications

(24 citation statements)

References 120 publications

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“…The osteogenic differentiation of MSCs is a complex process involving numerous signal molecules, including key transcription factors such as runt-related transcription factor 2 (Runx2) and Osterix, as well as various hormones. 7–11 In addition, the Wnt/β-catenin, bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) signaling pathways are indispensable during the osteogenic process. 12–15 Recently, accumulating evidence has shown that epigenetic regulation plays a pivotal role in the osteogenic differentiation of MSCs.…”

Section: Introductionmentioning

confidence: 99%

AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs

et al. 2017

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AFF1 and AFF4 belong to the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongation complexes (SECs). Both AFF1 and AFF4 regulate gene transcription through elongation and chromatin remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells (MSCs) is unknown. In this study, we show that small interfering RNA (siRNA)-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase (ALP) activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFF1 regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFF1-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.

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Section: Introductionmentioning

confidence: 99%

AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs

et al. 2017

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“…FGF23 is produced primarily by osteoblasts and osteocytes; however, it can be pathologically upregulated in other disease states such as hypertrophic cardiomyopathy . Indeed it has been long argued that the increases in FGF23 are causal for cardiac hypertrophy, although via Klotho‐independent processes.…”

Section: Fgf23 Chronic Kidney Disease and Cardiac Hypertrophymentioning

confidence: 99%

“…FGF23 is produced primarily by osteoblasts and osteocytes; however, it can be pathologically upregulated in other disease states such as hypertrophic cardiomyopathy. (4) Indeed it has been long argued that the increases in FGF23 are causal for cardiac hypertrophy, (25) although via Klotho-independent processes. However, recent studies using mouse models of FGF23 knockout and upregulation do not support this supposition, (26,27) and individuals with primarily FGF23-related hypophosphatemic bone disease do not consistently present with ventricular hypertrophy.…”

Section: Fgf23 Chronic Kidney Disease and Cardiac Hypertrophymentioning

confidence: 99%

“…FGF23 has emerged as a key regulatory factor for phosphate homeostasis and has been linked with a range of clinical conditions . FGF23 is produced primarily in bone, while its primary hormonal function is to regulate phosphate homeostasis and vitamin D metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…(3) FGF23 has emerged as a key regulatory factor for phosphate homeostasis and has been linked with a range of clinical conditions. (4) FGF23 is produced primarily in bone, while its primary hormonal function is to regulate phosphate homeostasis and vitamin D metabolism. This review will outline the role of FGF23 as a regulator of circulating phosphate levels via pathways involving its co-receptor Klotho, activated vitamin D, and parathyroid hormone (PTH); the role of FGF23 in heart and kidney disease, hypophosphatemic rickets, and other conditions associated with FGF23 dysregulation; and lastly emerging therapeutics for treating FGF23-mediated hypophosphatemia.…”

Section: Introductionmentioning

confidence: 99%

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FGF23, Hypophosphatemia, and Emerging Treatments

2019

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FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co‐receptor Klotho, it modulates phosphate reabsorption and both 1α‐hydroxylation and 24‐hydroxylation in the renal proximal tubules. The most common FGF23‐mediated hypophosphatemia is X‐linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23‐mediated forms of hypophosphatemia are characterized by phosphaturia and low or low‐normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23‐mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor‐induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23‐mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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