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Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity. NEW & NOTEWORTHY: There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23. [ABSTRACT FROM AUTHOR]

Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of drug resistance mutations at the gatekeeper residue hindering the access of the inhibitor to a hydrophobic pocket at the back of the ATP-binding cleft. In addition to reducing drug efficacy, gatekeeper mutations elevate the intrinsic activity of the tyrosine kinase domain leading to more aggressive types of cancer. However, the mechanism of gain-of-function by gatekeeper mutations is poorly understood. Here, we characterized fibroblast growth factor receptor (FGFR) tyrosine kinases harboring two distinct gatekeeper mutations using kinase activity assays, NMR spectroscopy, bioinformatic analyses, and MD simulations. Our data show that gatekeeper mutations destabilize the autoinhibitory conformation of the DFG motif locally and of the kinase globally, suggesting they impart gain-of-function by facilitating the kinase's ability to populate the active state. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation (1, 2). Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis (3, 4). Here we show that parenteral delivery of a single dose of recombinant FGF1(rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes., Increases in the prevalence of obesity and insulin resistance and the associated incidence of difficult-to-manage type 2 diabetes have become world-wide public health problems as well as a financial burden [...]

The ageing suppressor -klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of -klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, -klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of -klotho is incompatible with its purported glycosidase activity. Thus, shed -klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling., Author(s): Gaozhi Chen [1, 2]; Yang Liu [2]; Regina Goetz [2]; Lili Fu [1, 2]; Seetharaman Jayaraman [3]; Ming-Chang Hu [4]; Orson W. Moe [4]; Guang Liang [1]; Xiaokun Li [...]

The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and 'normal' intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas, Introduction Decades of clinical research in patients with solid tumors have demonstrated that complete and durable tumor regressions are rare. Indeed the clinical experience with chemotherapy for most solid tumor [...]

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in [FGFR3.sup.-/-] and [FGFR4.sup.-/-] null mice, and in conditional [FGFR1.sup.-/-] mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between [FGFR1.sup.-/-], [FGFR3.sup.-/-], and [FGFR4.sup.-/-] mice and their wild-type counterparts. Administration of FGF23 to [FGFR3.sup.-/-] mice induced hypophosphatemia in these mice (8.0 [+ or -] 0.4 vs. 5.4 [+ or -] 0.3 mg/dl; p [less than or equal to] 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in [FGFR4.sup.-/-] mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 [+ or -] 0.3 vs. 7.6 [+ or -] 0.4 mg/dl; p [+ or -] 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into [FGFR1.sup.-/-] mice had no effects on serum phosphorus levels (5.6 [+ or -] 0.3 vs. 5.2 [+ or -] 4- 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role. phosphaturia; phosphorus; proximal tubule

Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism. Fgf-[23.sup.-/-] or [Klotho.sup.-/- ] knockout mice exhibit several pathophysiological processes consistent with premature aging including severe atrophy of tissues. We show that the signal transduction pathways initiated by FGF-23--Klotho prevent tissue atrophy by stimulating proliferation and preventing apoptosis caused by excessive systemic vitamin D. Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1 [alpha]-hydroxylase expression and phosphoinositide-3 kinase--dependent inhibition of caspase activity. These data provide new insights into the physiological roles of FGF-23 and Klotho.

Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adult-onset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling., Introduction Vertebrate reproduction depends upon the secretion of gonadotropin-releasing hormone (GnRH), a decapeptide produced by a small number of GnRH neurons in the preoptic area (1). The coordinated pulsatile release [...]

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis., Introduction FGF23 is secreted by osteocytes (1) and osteoblasts (2) in response to high serum phosphate levels and after the administration of the vitamin D metabolite, 1,25[(OH).sub.2]-vitamin D (2-4). FGF23 [...]

Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivatingmutations in FGF23 or UDP-N-acetyl-[alpha]-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3(GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO [...]

Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine factor that stimulates glucose uptake in adipocytes. Here, we show that FGF21 activity depends on [beta]Klotho, a single-pass transmembrane protein whose expression is induced during differentiation from preadipocytes to adipocytes. [beta]Klotho physically interacts with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF21 and activate the MAP kinase cascade. Knockdown of [beta]Klotho expression by siRNA in adipocytes diminishes glucose uptake induced by FGF21. Importantly, administration of FGF21 into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without [beta]Klotho expression. Thus, [beta]Klotho functions as a cofactor essential for FGF21 activity. Klotho | glucose | adipocyte | siRNA | GLUT1

Idiopathic hypogonadotropic hypogonadism (IHH) due to defects of gonadotropin-releasing hormone (GnRH) secretion and/or action is a developmental disorder of sexual maturation. To date, several single-gene defects have been implicated in [...]

The fibroblast growth factor (FGF) family has 22 structurally related proteins. Each has a core region of homology of 100-120 residues in addition to N- and C- terminal regions.