Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D 3 . FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signalregulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition. 21: 112521: -113521: , 201021: . doi: 10.1681 Fibroblast growth factor 23 (FGF23) is produced by bone cells and plays a fundamental role in the regulation of mineral metabolism. FGF23 inhibits tubular resorption of phosphate and decreases 1␣ hydroxylase activity, which limits 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] production. Both phosphate excess and high 1,25(OH) 2 D 3 stimulate the production of FGF23. 1 FGF23 signals through a widely expressed receptor (FGFR) that becomes functional only in cells expressing the Klotho protein. 2,3 Klotho, which is expressed in the parathyroid cell, converts FGFR1(IIIc), a canonical receptor for various FGFs, into a specific receptor for FGF23. The tissue-specific unique biological activity of FGF23 is likely to be regulated by the limited local distribution of Klotho. In renal failure, the decrease in glomerular filtration causes phosphate retention, which stimulates the production of FGF23. This elevation in FGF23 levels should help to control phosphate in patients with renal failure. 4 J Am Soc Nephrol

The present study investigates the differential effect of two vitamin D receptor agonists, calcitriol and paricalcitol, on human aortic smooth muscle cells calcification in vitro. Human vascular smooth muscle cells were incubated in a high phosphate (HP) medium alone or supplemented with either calcitriol 10(-8)M (HP + CTR) or paricalcitol 3·10(-8) M (HP + PC). HP medium induced calcification, which was associated with the upregulation of mRNA expression of osteogenic factors such as bone morphogenetic protein 2 (BMP2), Runx2/Cbfa1, Msx2, and osteocalcin. In these cells, activation of Wnt/β-catenin signaling was evidenced by the translocation of β-catenin into the nucleus and the increase in the expression of direct target genes as cyclin D1, axin 2, and VCAN/versican. Addition of calcitriol to HP medium (HP + CTR) further increased calcification and also enhanced the expression of osteogenic factors together with a significant elevation of nuclear β-catenin levels and the expression of cyclin D1, axin 2, and VCAN. By contrast, the addition of paricalcitol (HP + PC) not only reduced calcification but also downregulated the expression of BMP2 and other osteoblastic phenotype markers as well as the levels of nuclear β-catenin and the expression of its target genes. The role of Wnt/β-catenin on phosphate- and calcitriol-induced calcification was further demonstrated by the inhibition of calcification after addition of Dickkopf-related protein 1 (DKK-1), a specific natural antagonist of the Wnt/β-catenin signaling pathway. In conclusion, the differential effect of calcitriol and paricalcitol on vascular calcification appears to be mediated by a distinct regulation of the BMP and Wnt/β-catenin signaling pathways.

This study examined the effects of the intensity and duration of exercise on the nature and magnitude of training adaptations in muscle of adolescent (2-3 yr old) racehorses. Six thoroughbreds that had been pretrained for 2 mo performed six consecutive conditioning programs of varying lactate-guided intensities [velocities eliciting blood lactate concentrations of 2.5 mmol/l (v2.5) and 4 mmol/l (v4), respectively] and durations (5, 15, 25 min). Pre- and posttraining gluteus muscle biopsies were analyzed for myosin heavy chain content, fiber-type composition, fiber size, capillarization, and fiber histochemical oxidative and glycolytic capabilities. Although training adaptations were similar in nature, they varied greatly in magnitude among the different training protocols. Overall, the use of v4 as the exercise intensity for 25 min elicited the most consistent training adaptations in muscle, whereas the minimal training stimulus that evoked any significant change was identified with exercises of 15 min at v2.5. Within this range, muscular adaptations showed significant trends to be proportional to the exercise load of specific training programs. Taken together, these data suggest that muscular adaptations to training in horses occur on a continuum that is based on the exercise intensity and duration of training. The practical implications of this study are that exercises for 15 to 25 min/day at velocities between v2.5 and v4 can improve in the short term (3 wk) the muscular stamina in thoroughbreds. However, exercises of 5-15 min at v4 are necessary to enhance muscular features related to strength (hypertrophy).

Because both metabolic (Met Acid) and respiratory acidosis (Resp Acid) have diverse effects on mineral metabolism, it has been difficult to establish whether acidosis directly affects parathyroid hormone (PTH) secretion. Our goal was to determine whether acute Met Acid and Resp Acid directly affected PTH secretion. Three groups of dogs were studied: control, acute Met Acid induced by HCl infusion, and acute Resp Acid induced by hypoventilation. EDTA was infused to prevent acidosis-induced increases in ionized calcium, but more EDTA was needed in Met Acid than in Resp Acid. The PTH response to EDTA-induced hypocalcemia was evaluated also. Magnesium needed to be infused in groups receiving EDTA to prevent hypomagnesemia. The half-life of intact PTH (iPTH) was determined during hypocalcemia when PTH was measured after parathyroidectomy. During normocalcemia, PTH values were greater (p < 0.05) in Met Acid (92 ؎ 19 pg/ml) and Resp Acid (77 ؎ 22 pg/ml) than in controls (27 ؎ 5 pg/ml); the respective pH values were 7.23 ؎ 0.01, 7.24 ؎ 0.01, and 7.39 ؎ 0.02. The maximal PTH response to hypocalcemia was greater (p < 0.05) in Met Acid (443 ؎ 54 pg/ml) than in Resp Acid (267 ؎ 37 pg/ml) and controls (262 ؎ 48 pg/ml). The half-life of PTH was greater (p < 0.05) in Met Acid than in controls, but the PTH secretion rate also was greater (p < 0.05) in Met Acid than in the other two groups. In conclusion, (

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