Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23-/-) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH)2D3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23-/- mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23-/- mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23-/- mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23-/- animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23/-/ mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hyp mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder.

The provisional criteria and algorithm appear to be useful for clarifying the entity of IgG4-RKD and seeking underlying IgG4-RKD cases; however, further experience is needed to confirm the validity of these criteria.

Fibroblast growth factor 23 null mice (Fgf-23 −/− ) have a short lifespan and show numerous biochemical and morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, and atrophy of the intestinal villi, skin, thymus, and spleen. Aging is a complex biological process controlled by multiple genetic and environmental factors (1-4). Studies involving molecular mechanisms of human aging and its progression are challenging, as it takes decades to develop some of the age-related features. Since extensive subsets of age-associated phenotypes define human aging, the availability of animal models exhibiting multiple aging features are useful, not only to analyze the molecular mechanisms of age-related changes in various organs, but also for the in vivo screening of molecules that counteract age-associated syndromes including anti-oxidant agents and hormones (5,6). DNA damage through oxidative stress, among others, is thought to be an important contributing factor in aging, and has been extensively studied in animals (1,3,(7)(8)(9)(10)(11). However, the potential role of humoral factor(s) regulating the aging process has not been studied in similar depth and detail. In this study, we show that genetic ablation of Fgf-23 results in a syndrome that resembles premature aging. (12,19,20).In this study, using in vivo genetic manipulation approaches, we present a novel role of Fgf-23 in premature aging and show that the premature aging-like phenotype in Fgf-23 −/− mice is partly mediated through increased vitamin D activities. MATERIALS AND METHODS Experimental miceWe recently generated . Animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were employed using protocols approved by the institution's subcommittee on animal care (IACUC). Macroscopic phenotypeThe total body weight of all mice was taken every 3-5 days starting at 2.5 wk of age until death. Survival of various groups of animals was recorded until death of control, Fgf-23 −/− , and double mutant Fgf-23 −/− /1α(OH)ase −/− mice. Biochemical measurementsBlood was obtained either by retro-orbital or tail bleeding of 3-, 6-, 9-and 11-wk-old wildtype, Fgf-23 −/− , and Fgf-23 −/− /1α(OH)ase −/− littermates. Serum was isolated by centrifugation at 3000 g for 10 min and stored at −80°C. Serum phosphorus and serum calcium were determined by colorometric measurements using the Stanbio Phosphorus Liqui-UV Test and Calcium (Arsenazo) LiquiColor Test, respectively. Total blood of 4-wk-old mice was used to determine routine hematological parameters such as cell counts. Skeletal analysesSkeletal changes in Fgf-23 −/− mice and their control littermates were analyzed by X-ray, quantitative CT (pQCT) and PIXImus measurements. Alizarin red S staining of total body skeletons, routine histology, and von Kossa staining were executed as described in our earlier studies (22). Immunohistochemica...

A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes of fibroblast growth factor 23 (Fgf23) and klotho ablated mice, which led to identification of klotho as an Fgf23 signaling cofactor. Here, we generated Fgf23 and klotho double-knockout (Fgf23(-/-)/klotho(-/-)) mice to test the hypothesis whether Fgf23 has a klotho-independent function. Fgf23(-/-)/klotho(-/-) mice are viable and have high serum phosphate levels, similar to Fgf23(-/-) and klotho(-/-) single-knockout mice. In addition, the Fgf23(-/-)/klotho(-/-) mice have increased renal expression of the sodium/phosphate cotransporter NaP(i)2a and of 1- alpha-hydroxylase concomitant with increased serum levels of 1,25-dihydroxyvitamin-D, as also observed in the Fgf23(-/-) and klotho(-/-) mice. Moreover, Fgf23(-/-)/klotho(-/-) mice show soft tissue and vascular calcification, severe muscle wasting, hypogonadism, pulmonary emphysema, distention of intestinal wall, and skin atrophy, all of which are also seen in Fgf23(-/-) and klotho(-/-) mice. Notably, injection of bioactive FGF23 protein into Fgf23(-/-)/klotho(-/-) and klotho(-/-) mice does not lower serum phosphate, whereas in wild-type and Fgf23(-/-) mice, it reduces serum phosphate. Together, these results provide compelling evidence that Fgf23 does not have a klotho-independent role in the regulation of systemic phosphate and vitamin D homeostasis.

Cisplatin (cis-diamminedichloroplatinum(II)) is an effective chemotherapeutic agent, and is successfully used in the treatment of a wide range of tumors. Despite its effectiveness as an anti-tumor drug, nephrotoxic side effects have significantly restricted its clinical use. Tubular epithelial cell deletion following cisplatin treatment is a major cause of renal injury. Oxidative stress significantly contributes to cisplatin-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of cisplatin. The renal microenvironmental changes following cisplatin treatment is a complex process and could be broadly categorized into three main pathological events, which at times might overlap: initial cytotoxic events, inflammatory events and fibroproliferative events. Stress responses and heat shock proteins generated following cisplatin treatment are actively involved in the initiation and progression of these events. In this article, we will briefly summarize factors involved in various phases of cisplatin-induced renal injuries.