FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating (Pi-regulating) hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth, and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone-specific deletion of Fgf23 on bone and mineral metabolism in the dentin matrix protein 1-knockout (Dmp1KO) mouse model of ARHR. At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency contributed to impaired mineralization independent of FGF23 or Pi levels. In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.

Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease.

Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.

DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease.

During chronic kidney disease (CKD), alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality. The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization, but its effects in CKD are unknown. We tested the hypothesis that DMP1 supplementation in CKD would improve bone health, prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes. We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3-/- mouse model of CKD. Col4a3-/- mice demonstrated impaired kidney function, reduced bone DMP1 expression, reduced bone mass, altered osteocyte morphology and connectivity, increased osteocyte apoptosis, increased serum FGF23, hyperphosphatemia, left ventricular hypertrophy (LVH), and reduced survival. Genetic or pharmacological supplementation of DMP1 in Col4a3-/- mice prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription, and further increased serum phosphate. Despite impaired kidney function and worsened hyperphosphatemia, DMP1 prevented development of LVH and improved Col4a3-/- survival. Our data suggest that CKD reduces DMP1 expression, whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

Inflammation regulates fibroblast growth factor 23 production.

PURPOSE OF REVIEW: Fibroblast growth factor 23 (FGF23) is a hormone secreted by osteocytes and osteoblasts that regulates phosphorus and vitamin D homeostasis. FGF23 levels increase progressively in chronic kidney disease (CKD), and FGF23 excess might be a causal factor of left ventricular hypertrophy, CKD progression and death. Therefore, understanding the molecular mechanisms that control FGF23 production is critical to design therapies to lower FGF23 levels. The present review focuses on the role of inflammatory stimuli on FGF23 regulation and summarizes recent studies that support a novel framework linking inflammation to FGF23 regulation. RECENT FINDINGS: Inflammation and iron deficiency, which are common occurrences in CKD, have emerged as novel FGF23 regulators. Recent findings show that inflammation increases FGF23 production in bone through direct and iron-related indirect mechanisms. In these settings, hypoxia-inducible factor (HIF)-1α orchestrates FGF23 transcription in response to inflammation and is primarily responsible for coordinating FGF23 production and cleavage. SUMMARY: We demonstrate that inflammation increases FGF23 production and may contribute to elevated FGF23 levels in CKD. Osseous HIF-1α may represent a therapeutic target to lower FGF23 levels in CKD patients and minimize the negative consequences associated with FGF23 excess.

Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease.

Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone of putative bone origin that is elevated in patients with chronic kidney disease (CKD). The mechanisms responsible for elevations of FGF23 and its role in the pathogenesis of chronic kidney disease-mineral bone disorder (CKD-MBD) remain uncertain. We investigated the association between FGF23 serum levels and kidney disease progression, as well as the phenotypic features of CKD-MBD in a Col4a3 null mouse model of human autosomal-recessive Alport syndrome. These mice exhibited progressive renal failure, declining 1,25(OH)(2)D levels, increments in parathyroid hormone (PTH) and FGF23, late-onset hypocalcemia and hyperphosphatemia, high-turnover bone disease, and increased mortality. Serum levels of FGF23 increased in the earliest stages of renal damage, before elevations in blood urea nitrogen (BUN) and creatinine. FGF23 gene transcription in bone, however, did not increase until late-stage kidney disease, when serum FGF23 levels were exponentially elevated. Further evaluation of bone revealed trabecular osteocytes to be the primary cell source for FGF23 production in late-stage disease. Changes in FGF23 mirrored the rise in serum PTH and the decline in circulating 1,25(OH)(2)D. The rise in PTH and FGF23 in Col4a3 null mice coincided with an increase in the urinary fractional excretion of phosphorus and a progressive decline in sodium-phosphate cotransporter gene expression in the kidney. Our findings suggest elevations of FGF23 in CKD to be an early marker of renal injury that increases before BUN and serum creatinine. An increased production of FGF23 by bone may not be responsible for early increments in FGF23 in CKD but does appear to contribute to FGF23 levels in late-stage disease. Elevations in FGF23 and PTH coincide with an increase in urinary phosphate excretion that likely prevents the early onset of hyperphosphatemia in the face of increased bone turnover and a progressive decline in functional renal mass.

Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway.

Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with ip leptin at two different doses or vehicle for 14 d. In tail-suspended rats, low-dose leptin compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by three-dimensional microtomography). In contrast, high-dose leptin inhibited femoral bone growth and reduced bone mass by decreasing bone formation rate and increasing bone resorption in both tail-suspended and unsuspended groups. High- and low-dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High-dose leptin (but not low) induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone changes at high-dose leptin are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by additional studies.