Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia

Leifheit-Nestler, Maren; Kucka, Julia; Yoshizawa, Emi; Behets, Geert J.; D’Haese, Patrick C.; Bergen, Christian; Meier, Martin; Fischer, Dagmar‐Christiane; Haffner, Dieter

doi:10.1016/j.bone.2017.06.019

Cited by 8 publications

(9 citation statements)

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“…Therefore, the question arises if alterations in the mineral metabolism may modulate the cardiac phenotype in these two mouse models. In line with previous published studies by others ( 37 , 55 ) and us ( 46 ), Hyp mice showed normal to reduced serum calcium levels, presented with hypophosphatemia, secondary hyperparathyroidism, and vitamin D deficiency. In contrast, kl/kl mice were hypercalcemic and hyperphosphatemic, had elevated 1,25D levels, and suppressed serum PTH levels ( 44 , 45 ).…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, Hyp mice showed 6.5-fold enhanced serum PTH concentrations compared to WT animals (Figure 6 C), whereas previous reports describe suppressed PTH levels in kl/kl mice ( 44 , 45 ). Others and we showed previously that Hyp mice are deficient for 1,25D, whereas kl/kl mice have significantly higher serum 1,25D levels ( 37 , 44 – 46 ). Finally, Hyp mice showed markedly reduced renal Klotho mRNA expression levels (0.6 ± 0.07-fold; P = 0.0012), which were barely detectable in renal tissue of kl/kl mice (Figure 6 D).…”

Section: Resultsmentioning

confidence: 51%

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Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

et al. 2018

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Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal link has not been established so far. Here, we investigated the cardiac phenotype in klotho hypomorphic (kl/kl) mice and Hyp mice, two mouse models of elevated FGF23 levels and klotho deficiency, but differing in parameters of mineral metabolism, by using histology, quantitative real-time PCR, immunoblot analysis, and serum and urine biochemistry. Additionally, the specific impact of calcium, phosphate, PTH, and 1,25D on hypertrophic growth of isolated neonatal rat cardiac myocytes was investigated in vitro. Kl/kl mice displayed high serum Fgf23 levels, increased relative heart weight, enhanced cross-sectional area of individual cardiac myocytes, activated cardiac Fgf23/Fgf receptor (Fgfr) 4/calcineurin/nuclear factor of activated T cell (NFAT) signaling, and induction of pro-hypertrophic NFAT target genes including Rcan1, bMHC, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) as compared to corresponding wild-type (WT) mice. Investigation of fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated ERK1/2 activation and enhanced expression of Tgf-β1, collagen I, and Mmp2 in kl/kl mice than in WT mice. In contrast, despite significantly elevation of serum and cardiac Fgf23, and reduced renal klotho expression, Hyp mice showed no signs of pathological cardiac remodeling. Kl/kl mice showed enhanced serum calcium and phosphate levels, while Hyp mice showed unchanged serum calcium levels, lower serum phosphate, and elevated serum iPTH concentrations compared to corresponding WT mice. In cultured cardiac myocytes, treatment with both calcium or phosphate significantly upregulated endogenous Fgf23 mRNA expression and stimulated hypertrophic cell growth and expression of pro-hypertrophic genes. The treatment with PTH induced hypertrophic cell growth only, and stimulation with 1,25D had no significant effects. In conclusion, our data indicate that Hyp mice, in contrast to kl/kl mice appear to be protected from pathological cardiac remodeling during conditions of high FGF23 levels and klotho deficiency, which may be due, at least in part, to differences in mineral metabolism alterations, i.e., hypophosphatemia and lack of hypercalcemia.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 51%

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

et al. 2018

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“…Recent additions to the long list of factors proposed to affect FGF23 expression include actin cytoskeleton reorganisation, NFκB signalling [29], aldosterone [30], ORAI1 [31], changes in calcium concentrations, activated renin angiotensin system, KLOTHO [32], and local osteoblastic conversion of 25(OH)D to calcitriol [33].…”

Section: Background and Introductionmentioning

confidence: 99%

FGF23 and its role in X-linked hypophosphatemia-related morbidity

Beck-Nielsen

Mughal

Haffner

et al. 2019

Orphanet J Rare Dis

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Background X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked ( PHEX ) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood. Methods The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH. Results The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations. Conclusions By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.

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“…Moreover, a case report described that the addition of cinacalcet reduced PTH and calcium levels and increased serum phosphate, as was expected, but also reduced FGF-23 levels, which remained stable after 6 months of therapy [82]. However, in a recent study in Hyp mice an orthogous animal model of XLH, monotherapy with cinacalcet (R568) reduced PTH and FGF-23 synthesis in bone but failed to restore vitamin D and phosphate metabolism and skeletal abnormalities [83]. Therefore, long-term clinical trials should be conducted in order to investigate cinacalcet's potential as an adjuvant treatment of XLH [62].…”

Section: Calcimimetics and Thiazide Diuretics Or Amiloride In Xlhmentioning

confidence: 79%

Phosphate wasting disorders in adults

et al. 2018

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A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.

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Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia

Cited by 8 publications

References 44 publications

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

FGF23 and its role in X-linked hypophosphatemia-related morbidity

Phosphate wasting disorders in adults

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