Emerging role of fibroblast growth factor 23 in a bone–kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization

Liu, Shiguang; Gupta, Aditi; Quarles, L. Darryl

doi:10.1097/mnh.0b013e3281ca6ffd

Cited by 112 publications

(82 citation statements)

References 74 publications

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“…2) FGF23 is produced mainly in osteoblasts in the early stage, but comes to be seen predominantly in osteocytes in the later stages of metaphyseal trabeculae and cortical bones. Sclerostin and FGF23 have been known as osteocyte-derived factors (22,28,35,39,41,42). However, this study revealed the different distribution of sclerostin/FGF23 between the close and distant regions of metaphyseal trabeculae.…”

Section: Discussioncontrasting

confidence: 47%

“…Although Fgf23 mRNA was found in several tissues (1,21,34), it was most abundantly expressed in bone (41). As a circulating growth factor, FGF23 inhibits phosphate reabsorption and 1α,25(OH) 2 D 3 production in the kidney (22), thus acting on serum homeostasis of phosphate and calcium. In brief, sclerostin and FGF23 are secreted by osteocytes and appear to be involved in bone metabolism in adult stages, i.e., are involved in normal bone remodeling and serum mineral balance.…”

Section: Methodsmentioning

confidence: 99%

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Chronological immunolocalization of sclerostin and FGF23 in the mouse metaphyseal trabecular and cortical bone

et al. 2017

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To assess the chronological participation of sclerostin and FGF23 in bone metabolism, this study tracked the immunolocalization of sclerostin and FGF23 in the metaphyses of murine long bones from embryonic day 18 (E18) through 1 day after birth, 1 week, 2 weeks, 4 weeks, 8 weeks, and 20 weeks of age. We have selected two regions in the metaphyseal trabeculae for assessing sclerostin and FGF23 localization: close to the chondro-osseous junction, i.e., bone modeling site even in the adult animals, and the trabecular region distant from the growth plate, where bone remodeling takes place. As a consequence, sclerostin-immunopositive osteocytes could not be observed in both close and distant trabecular regions early at the embryonic and young adult stages. However, osteocytes gradually started to express sclerostin in the distant region earlier than in the close region of the trabeculae. Immunoreactivity for FGF23 was observed mainly in osteoblasts in the early stages, but detectable in osteocytes in the later stages of growth in trabecular and cortical bones. Fgf23 was weakly expressed in the embryonic and neonatal stages, while the receptors, Fgfr1c and αKlotho were strongly expressed in femora. At the adult stages, Fgf23 expression became more intense while Fgfr1c and aKlotho were weakly expressed. These findings suggest that sclerostin is secreted by osteocytes in mature bone undergoing remodeling while FGF23 is synthesized by osteoblasts and osteocytes depending on the developmental/growth stage. In addition, it appears that FGF23 acts in an autocrine and paracrine fashion in fetal and neonatal bones.By establishing a communication network between osteocytes and osteoblasts, osteocytes are situated at the center of bone turnover and help determine how bones adjust to mechanical stress through bone remodeling. Osteocytes exist inside osteocytic lacunae and connect to neighboring osteocytes and osteoblasts on the bone surfaces via fine cytoplasmic processes that run through osteocytic canaliculi. Osteocytes interconnect their cytoplasmic processes via gap junctions (2,6,7,33), thereby building functional syncytia referred to as osteocytic lacunar-canalicular system (OLCS) (5,15,16,31). In the last few decades, many studies have reported on important osteocyte-derived factors, such as sclerostin (which regulates osteoblastic activities) and fibroblast growth factor 23 (FGF23, which affects the proximal renal tubules to reduce serum

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Section: Discussioncontrasting

confidence: 47%

Section: Methodsmentioning

confidence: 99%

Chronological immunolocalization of sclerostin and FGF23 in the mouse metaphyseal trabecular and cortical bone

et al. 2017

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“…However, the major player of the bone-kidney axis controlling phosphate homeostasis has been shown to be fibroblast growth factor 23 (FGF23). FGF23 acts as a phosphaturic factor by the same mechanism of action as PTH, downregulating the co-transporters NaPi2a and NaPi2c in the kidney after binding to its receptor, FGFR1, in the presence of Klotho (9)(10)(11). FGF23 also decreases 1,25(OH) 2 D synthesis in the proximal tubules by direct inhibition of the 1a-hydroxylase enzyme (9,10,12).…”

Section: Introductionmentioning

confidence: 99%

“…FGF23 is predominantly produced and secreted by osteocytes in bone (9,10). This process is positively regulated by 1,25(OH) 2 D, via a vitamin D response element in the fgf23 promoter (9,(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?

Witteveen

Lierop

Papapoulos

et al. 2012

European Journal of Endocrinology

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Introduction: Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are major players in the bone-parathyroid-kidney axis controlling phosphate homeostasis. In patients with primary hyperparathyroidism (PHPT), data on the relationship between PTH and FGF23 are scarce and not always concordant. Objective: The aim of our study was to evaluate the relationship between PTH and FGF23 in patients with PHPT and in euparathyroid patients cured after successful parathyroidectomy (PTx). Patients and methods: Twenty-one patients with PHPT and 24 patients in long-term cure after successful PTx (EuPTH) were studied. All patients underwent biochemical evaluation of renal function, parathyroid status, vitamin D status, bone turnover markers, and serum intact FGF23 levels. Results: Mean serum FGF23 concentration was significantly higher in PHPT than in EuPTH patients (50.8G6.1 vs 33.1G2.6 pg/ml, PZ0.01). FGF23 levels significantly correlated with PTH levels (rZ 0.361, PZ0.02), also after correction for 1,25(OH) 2 D levels (rZ0.419, PZ0.01). FGF23 levels showed a significant negative correlation with 1,25(OH) 2 D, which was more pronounced in PHPT than in EuPTH patients (rZK0.674, PZ0.001, vs rZK0.509, PZ0.01). Conclusion: Our findings suggest that in PHPT, FGF23 levels are increased independent of 1,25(OH) 2 D levels. The more pronounced negative relationship between FGF23 and 1,25(OH) 2 D in the presence of high circulating PTH levels suggests that the increase in FGF23 levels may be an adaptive mechanism to counteract the PTH-induced increase in 1,25(OH) 2 D levels, although not completely overriding it.

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“…FGF23 downregulates matrix proteins, such as osteocalcin and sialoprotein, which are both required for osteogenesis and reduces 1-alpha-hydroxylase vitamin D levels, resulting in hypophosphatemia, renal phosphate wastage and osteomalacia (Liu et al 2007, Tenenhouse 2007.…”

mentioning

confidence: 99%

Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts

Silva

Tempone

Silva

et al. 2010

Mem. Inst. Oswaldo Cruz

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Emerging role of fibroblast growth factor 23 in a bone–kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization

Cited by 112 publications

References 74 publications

<b>Chronological immunolocalization of sclerostin and FGF23 in the mouse metaphyseal trabecular and cortical </b><b>bone </b>

<b>Chronological immunolocalization of sclerostin and FGF23 in the mouse metaphyseal trabecular and cortical </b><b>bone </b>

Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?

Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts

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