Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process - PubMed (original) (raw)

Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process

Mohammed S Razzaque et al. FASEB J. 2006 Apr.

Abstract

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. Furthermore, increased vitamin D activities in homozygous mutants are associated with severe atherosclerosis and widespread soft tissue calcifications; ablation of vitamin D activity from Fgf-23-/- mice, by genetically deleting the 1alpha(OH)ase gene, eliminates atherosclerosis and ectopic calcifications and significantly rescues premature aging-like features of Fgf-23-/- mice, resulting in prolonged survival of Fgf-23-/-/1alpha(OH)ase-/- double mutants. Our results indicate a novel role of Fgf-23 in developing premature aging-like features through regulating vitamin D homeostasis. Finally, our data support a new model of interactions among Fgf-23, vitamin D, and klotho, a gene described as being associated with premature aging process.

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Figures

Figure 1

Figure 1

Premature aging features of _Fgf-23_−/− mice. A) Mutant mouse (top) shows small body size, reduced muscle mass, and kyphosis when compared with normal control littermate (bottom) at 6 wk of age. B) Number of lymphocytes in peripheral blood of _Fgf-23_−/− animals (_n_=9, blue bar) was significantly decreased (P<0.0001), when compared with controls (_n_=13, red bar). C) Mitogenic response of T cells isolated from thymus, lymph nodes, or spleen to concavanalin A. Shown are mean values (quadruplicates) of controls (_n_=3, red circles) and _Fgf-23_−/− animals (_n_=2, blue squares). Red and blue cross-lines represent mean of 12 measurements in controls (red lines) and 8 measurements in mutants (blue lines). D) Atrophy of mutant uterus and ovary (right) when compared with normal (left) at 6 wk of age leads to hypogonadism and infertility in females. E) Atrophied testes of _Fgf-23_−/− animals (right) also causes infertility in _Fgf-23_−/− males. F) Quantitative assessment of the weight of spleen and thymus (_n_=3, P<0.05). Data are presented as fold over control (=1) after each organ weight was normalized to total body weight of matching animal. Macroscopic picture of an atrophied thymus (G) and spleen (H) of _Fgf-23_−/− animals (right) when compared with normal control littermates (left).

Figure 2

Figure 2

Macroscopic and microscopic features of various organs at 6 wk of age (_n_=8). Hematoxilin- and eosin stained sections of wild-type (A) and _Fgf-23_−/− (B) testes and of control (C) and _Fgf-23_−/− (D) lungs (A–D: ×10). Mutant lung exhibits typical emphysematous features as observed during aging. E) Toluidine blue staining of an _Fgf-23_−/− kidney at 6 wk of age. Arrows depict kidney stones found only in the mutants. F) Congo-red staining indicates amyloid deposition found in small and medium sized arteries of the mutant kidney and heart (H). G) von Kossa staining demonstrates severe calcification of the aortic wall in _Fgf-23_−/− animals. Macroscopic image of small intestine of wild-type (I) and _Fgf-23_−/− animal (J) (_n_=6), showing ballooning of mutant intestine. Hematoxilin/eosin staining of cross sections of wild-type (K) and _Fgf-23_−/− littermate (L) (K and L: ×5). Reduced height of intestinal villi, and atrophy of intestinal mucosa are shown. Immunohistochemical evaluation by α-smooth muscle actin antibody staining presents dramatic reduction in vascularization and smooth muscle coat in intestine of mutant animals (N), when compared with normal littermates M). BrdU staining demonstrates striking diminution of proliferative cells in mutants (P) vs. wild-type (O) mice (M to P: ×10). R) Increased apoptosis in the mutant skin is visible by positive TUNEL staining mostly located in hair follicles when compared with normal (Q). BrdU labeling of the skin resulted in dramatic decrease in proliferative cells in _Fgf-23_−/− (T) vs. normal (S) littermate (Q to T: ×10).

Figure 3

Figure 3

Ectopic calcifications. Von Kossa staining of paraffin sections of kidney (A), heart (C; muscle and valves), and lung of _Fgf-23_−/− (E) animals demonstrating severe calcifications of these organs. Images presented in B, D, and F show complete elimination of abnormal calcification pattern in littermates that are deficient for both Fgf-23 and 1α(OH)ase gene (_n_=8; A to F: ×10).

Figure 4

Figure 4

A) Macroscopic image of a wild-type (WT), _Fgf-23_−/−, and _Fgf-23_−/−/_1α(OH)ase_−/− double mutant at ~6 wk of age. B) Body weight curve and survival curve (C) of control, _Fgf-23_−/− and _Fgf-23_−/−/_1α (OH)ase_−/− mice (n_>15) showing gain of weight and prolonged lifespan in compound mutants. Hematoxilin/eosin staining of intestinal sections of wild-type (D), Fgf-23_−/− (F), and _Fgf-23_−/−/_1α(OH)ase_−/− double knockout animals. Single _Fgf-23_−/− mice exhibit (E) severe atrophy of intestine, which is significantly improved by deletion of the 1α(OH)ase gene. Similar improvement was also noted in the skin section of _Fgf-23_−/−/_1α(OH)ase_−/− double knockout animals, compared with _Fgf-23_−/− mice; wild-type (G), _Fgf_-23−/− (H), and _Fgf-23_−/−/_1α(OH)ase_−/− (I) double knockout animals (D to I: ×10).

Figure 5

Figure 5

A) Quantitative real-time PCR was performed for klotho expression in kidney (_n_>3). Relative expression of klotho mRNA in kidneys of _Fgf-23_−/− animals (P<0.01) and in _Fgf-23_−/−/_1α(OH)ase_−/− double knockout animals (P<0.05) is significantly decreased when compared with controls. Data shown is the klotho mRNA expression as fold over control (=1). B) Schematic representation of a model showing the possible interactions among Fgf-23, vitamin D, and klotho. Fgf-23 activity is required for vitamin-D mediated expression of klotho.

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