Dataset Information

Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels.

ABSTRACT: Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; however, the regulatory network of FGF23 in osteocytes has not yet been defined in detail. We herein investigated the role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in this regulation. We created mice lacking PTEN expression mainly in osteocytes by crossing Pten-flox mice with Dmp1-Cre mice. The lack of PTEN in the osteocytes of these mice was associated with decreased skeletal and serum intact FGF23 levels, which, in turn, resulted in reductions of urinary Pi excretion and elevations of serum Pi levels. Mechanistically, the knockdown of PTEN expression in osteoblastic UMR106 cells activated the AKT/mTORC1 (mechanistic target of rapamycin complex 1) pathway and this was associated with reductions in Fgf23 expression. Furthermore, the suppression of Fgf23 expression by PTEN knockdown or insulin simulation in UMR106 cells was partially restored by the treatment with the mTORC1 inhibitor, rapamycin. These results suggest that FGF23 expression in osteoblastic cells is in part regulated through the AKT/mTORC1 pathway and provide new insights into our understanding of the regulatory network of Pi metabolism.

SUBMITTER: Kawai M

PROVIDER: S-EPMC7726559 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels.

Kawai Masanobu M Kinoshita Saori S Ozono Keiichi K Michigami Toshimi T

Scientific reports 20201209 1

Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; however, the regulatory network of FGF23 in osteocytes has not yet been defined in detail. We herein investigated the role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in this regulation. We created mice lacking PTEN expression mainly in osteocytes by crossing Pten-flox mice with Dmp1-Cre mice. The lack of PTEN in the osteocytes of these mice was associated with decreased s ...[more]

PMID: 33299044

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Project description:Fibroblast growth factor-23 (FGF23), a bone-produced hormone, plays a critical role in mineral homeostasis. Human diseases associated with excessive intact circulating FGF23 (iFGF23) result in hypophosphatemia and low vitamin D hormone in patients with normal kidney function. In addition, there is accumulating evidence linking FGF23 with inflammation. Based on these studies and the frequent observation of hypophosphatemia among septic patients, we sought to elucidate further the relationship between FGF23 and mineral homeostasis in a clinically relevant murine polymicrobial sepsis model. Medium-severity sepsis was induced by cecum ligation puncture (CLP) in adult CD-1 mice of both sexes. Healthy CD-1 mice (without CLP) were used as controls. Forty-eight hours post-CLP, spontaneous urine was collected, and serum, organs and bones were sampled at necropsy. Serum iFGF23 increased ~20-fold in CLP compared to control mice. FGF23 protein concentration was increased in the bones, but not in spleen or liver of CLP mice. Despite the ~20-fold iFGF23 increase, we did not observe any significant changes in mineral homeostasis or parathyroid hormone levels in the blood of CLP animals. Urinary excretion of phosphate, calcium, and sodium remained unchanged in male CLP mice, whereas female CLP mice exhibited lower urinary calcium excretion, relative to healthy controls. In line with renal FGF23 resistance, expression of phosphate-, calcium- and sodium-transporting proteins did not show consistent changes in the kidneys of male and female CLP mice. Renal expression of the co-receptor αKlotho was downregulated in female, but not in male CLP mice. In conclusion, our data demonstrate that the dramatic, sex-independent rise in serum iFGF23 post-CLP was mainly caused by an upregulation of FGF23 secretion in the bone. Surprisingly, the upsurge in circulating iFGF23 did not alter humoral mineral homeostasis in the acutely septic mice. Hence, the biological function of elevated FGF23 in sepsis remains unclear and warrants further studies.

Project description:ObjectiveFibroblast growth factor 23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and is associated with coronary artery calcification, and has been implicated in the pathogenesis of cardiovascular disease. The aim of this study was to determine whether circulating FGF23 concentration is independently associated with the severity and extent of coronary artery disease in patients undergoing coronary angiography.MethodA cross-sectional design was used to examine the relationship between serum FGF23 and the severity and extent of coronary artery stenosis in 2076 patients undergoing coronary angiography (1263 male and 813 female, mean aged 62.5 years). Subgroup analyses were performed to assess the associations between FGF23 and coronary arterial plaque characteristics evaluated by intravascular ultrasound and 12-month incidence of target vessel revascularization (TVR) and target lesion revascularization (TLR).FindingsWe found a stepwise increase of serum FGF23 concentrations in patients with mild, moderate, severe stenosis or with increased number of stenotic vessels compared with those without stenosis (P<0.001). Serum FGF23 concentration was positively correlated with stenosis scores as the global index of the severity and extent of coronary artery stenosis in both male and female (r = 0.315 and r = 0.291, P<0.001). In multiple regression analyses, serum FGF23 concentration was a significant determinant of the stenosis scores independent of other traditional risk factors (standardized β = 0.326, P<0.001). Furthermore, subgroup analyses found FGF23 was significantly associated with plaque and dense calcium volumes. Multiple logistic regression analyses showed that serum FGF23 levels were significantly independent predictors of TVR and TLR.ConclusionsWe report an independent association between circulating FGF23 concentration and the severity and extent of coronary artery stenosis in the coronary angiographic patients. Future studies are needed to elucidate the potential biological mechanisms and whether FGF23 is a modifiable cardiovascular risk factor.

Dataset Information

Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels.

Publications

Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels.

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