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Herein, we demonstrated by Ussing chamber technique that male mice administered 1 g/kg 1,25(OH) 2D3 sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 1-4 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH) 2D3-induced calcium absorption in the duodenal tissues taken from the 1,25(OH) 2D3-treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH) 2D3 preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH) 2D3-induced upregulation of TRPV5, TRPV6, and calbindin-D 9k, but not PMCA1b expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH) 2D3-induced calcium absorption.calbindin-D 9k; fibroblast growth factor receptor; Klotho; transient receptor potential vanilloid type 6; Ussing chamber FIBROBLAST GROWTH FACTOR (FGF)-23 has been recognized as the osteoblast/osteocyte-derived phosphate-regulating hormone, a phosphatonin with phosphaturic and hypophosphatemic action (19,42,45 (29). Some hereditary and acquired diseases, e.g., autosomal dominant hypophosphatemic rickets/osteomalacia, tumor-induced osteomalacia, and X-linked hypophosphatemic rickets, result from abnormally high circulating FGF-23 activity. Dysregulation of FGF-23 action is also evident in various pathological conditions, such as chronic metabolic acidosis and chronic kidney disease (11,20).Once secreted from osteoblasts and osteocytes, FGF-23 exerts its phosphaturic action in the renal proximal tubular cells via the FGF receptor (FGFR)/Klotho coreceptor complex, thereby downregulating Na ϩ -dependent phosphate transporter (NPT)-2a and NPT-2c expression (14). Its intracellular signaling in renal epithelial cells is conveyed through a number of pathways, e.g., mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), p38 MAPK, phosphoinositide 3-kinase (PI3K)/Akt, and protein kinase C (PKC) (12,13,43). FGF-23 also downregulates renal 25-hydroxyvitamin D 1␣-hydroxylase (1-OHase; also known as Cyp27b1) and upregulates 24-hydroxylase (24-OHase, Cyp24a1), which are important enzymes for production and inactivation of 1,25(OH) 2 D 3 , respectively, thereby reducing circulating levels of 1,25(OH) 2 D 3 (35, 42). Since 1,25(OH) 2 D 3 is the cardinal regulator of intestinal cal...

The lactogenic hormone prolactin (PRL) directly regulates osteoblast functions in vitro and modulates bone remodeling in nulliparous rats, but its osteoregulatory roles in pregnant and lactating rats with physiological hyperprolactinemia remained unclear. Herein, bone changes were investigated in rats treated with bromocriptine (Bromo), an inhibitor of pituitary PRL release, or BromoϩPRL at different reproductive phases, from mid-pregnancy to late lactation. PRL receptors were strongly expressed in osteoblasts lining bone trabeculae, indicating bone as a target of PRL actions. By using dual energy X-ray absorptiometry, we found a significant increase in bone mineral density in the femora and vertebrae of pregnant rats. Such pregnancyinduced bone gain was, however, PRL independent and may have resulted from the increased cortical thickness. Bone trabeculae were modestly changed during pregnancy as evaluated by bone histomorphometry. On the other hand, lactating rats, especially in late lactation, showed massive bone loss in bone trabeculae but not in cortical shells. Further study in Bromo-and BromoϩPRL-treated rats suggested that PRL contributed to decreases in trabecular bone volume and number and increases in trabecular separation and eroded surface, as well as a paradoxical increase in bone formation rate in late lactation. Uncoupling of trabecular bone formation and resorption was evident in lactating rats, with the latter being predominant. In conclusion, pregnancy mainly induced cortical bone gain, whereas lactation led to trabecular bone loss in both long bones and vertebrae. Although PRL was not responsible for the pregnancy-induced bone gain, it was an important regulator of bone modeling during lactation. bone histomorphometry; hyperprolactinemia; ion chromatography; osteopenia; uncoupling IN PREGNANT AND BREASTFEEDING WOMEN, massive calcium loss occurs for fetal development (ϳ200 -300 mg/day) and lactogenesis (ϳ300 -1,000 mg/day), respectively (4,23,36). A huge amount of calcium demand is accomplished, in part, by enhanced intestinal calcium absorption during these reproductive periods (9). Our recent studies in rats demonstrated that the lactogenic hormone prolactin (PRL), released from the anterior pituitary gland during pregnancy (ϳ100 -200 ng/ml) and lactation (ϳ200 -300 ng/ml), was the principal calciotropic maternal hormone, which was capable of stimulating calcium absorption in the small intestine and proximal large intestine (7, 21). Moreover, lactation-induced bone resorption provides additional calcium to match the increased calcium demand of the offspring, which in turn induces reversible osteopenia in mothers (20,36).In both humans and rodents, hormonal regulation of bone changes during pregnancy and lactation is not completely understood, but it is not directly regulated by the major calciotropic hormones, namely parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] (9, 30, 36). Other hormones with elevated plasma levels, such as PRL, PTHrelated peptide (PTHrP), calcit...

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