Genetic Evidence of Serum Phosphate-Independent Functions of FGF-23 on Bone (original) (raw)
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Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2016
The transgenic and knock out (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened life span, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ('f')-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ('Δ') had undetectable serum intact FGF23, elevated serum phosphate (p < 0.05), and increased kidney Cyp27b1 mRNA (p < 0.05) similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge Fgf23(Δ/f) mice were mated with early osteoblast type Iα1 collagen 2.3kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(Δ/f) /Col2...
Matrix Biology, 2004
Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23 −/− ) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH) 2 D 3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23 −/− mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23 −/− mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23 −/− mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23 −/− mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23 −/− animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23 −/− mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hyp mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder.
Bone Mineralization and Regulation of Phosphate Homeostasis
The physiological process of biomineralization (calcification) that occurs in bone tissue takes place throughout an individual's life. Complex biological systems carefully orchestrating crosstalk between skeletal tissue and mineralization modulators include environmental and physiological factors acting as promoters or inhibitors. They consist of local mineralization promoters synthesized by osteoblasts, the phosphatases, namely, tissue-nonspecific alkaline phosphatase (TNAP) and phosphatase orphan 1 (PHOSPHO1). The local inhibitors are produced by osteoblasts and osteocytes and include inorganic pyrophosphate (PPi) and organic non-collagenous proteins or peptides of the extracellular matrix, such as osteopontin. While these modulators act in a paracrine/autocrine manner, locally synthesized fibroblast growth factor 23 (FGF23) regulates systemic phosphate levels by creating bone-kidney-parathyroid feedback loops. Locally, the active role in regulation of mineralization and phosphate homeostasis is played by inorganic forms of phosphate itself, and in particular the Pi/PPi ratio. The upper control of this ratio is mediated by circulating effects of FGF23 on phosphate homeostasis. Bone cell products allow bone to play an active role in coordinating its mineralization with total systemic phosphate regulation.
The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis
Nature Reviews Endocrinology, 2009
Appropriate levels of phosphate in the body are maintained by the coordinated regulation of the bone-derived growth factor FGF23 and the membrane-bound protein Klotho. The endocrine actions of FGF23, in association with parathyroid hormone and vitamin D, mobilize sodiumphosphate cotransporters that control renal phosphate transport in proximal tubular epithelial cells. The availability of an adequate amount of Klotho is essential for FGF23 to exert its phosphaturic effects in the kidney. In the presence of Klotho, FGF23 activates downstream signaling components that influence the homeostasis of phosphate, whereas in the absence of this membrane protein, it is unable to exert such regulatory effects, as demonstrated convincingly in animal models. Several factors, including phosphate and vitamin D, can regulate the production of both FGF23 and Klotho and influence their functions. In various acquired and genetic human diseases, dysregulation of FGF23 and Klotho is associated with vascular and skeletal anomalies owing to altered phosphate turnover. In this Review, I summarize how the endocrine effects of bonederived FGF23, in coordination with Klotho, can regulate systemic phosphate homeostasis, and how an inadequate balance of these molecules can lead to complications that are caused by abnormal mineral ion metabolism.
Journal of Endocrinology, 2007
Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of the fibroblast growth factor (FGF)-23–klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1α-hydroxylase and sodium–phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23–klotho axis in maintaining mineral ion homeostasis. In this brief article, we w...
EDUCATIONAL REVIEW Phosphate homeostasis and its role in bone health
2012
Phosphate is one of the most abundant minerals in the body, and its serum levels are regulated by a complex set of processes occurring in the intestine, skeleton, and kidneys. The currently known main regulators of phosphate homeostasis include parathyroid hormone (PTH), calcitriol, and a number of peptides collectively known as the “phos-phatonins ” of which fibroblast growth factor-23 (FGF-23) has been best defined. Maintenance of extracellular and intracellular phosphate levels within a narrow range is im-portant for many biological processes, including energy metabolism, cell signaling, regulation of protein synthesis, skeletal development, and bone integrity. The presence of adequate amounts of phosphate is critical for the process of apoptosis of mature chondrocytes in the growth plate. With-out the presence of this mineral in high enough quantities, chondrocytes will not go into apoptosis, and the normal physiological chain of events that includes invasion of blood vessels an...