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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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Suntornsaratoon P, Kraidith K, Teerapornpuntakit J, Dorkkam N, Wongdee K, Krishnamra N, Charoenphandhu N. Pre-suckling calcium supplementation effectively prevents lactation-induced osteopenia in rats. Am J Physiol Endocrinol Metab 306: E177-E188, 2014. First published December 3, 2013 doi:10.1152/ajpendo.00556.2013.-During lactation, osteoclast-mediated bone resorption and intestinal calcium hyperabsorption help provide extra calcium for lactogenesis. Since the suckling-induced surge of pituitary prolactin (PRL) rapidly stimulates calcium absorption in lactating rats, it is hypothesized that pre-suckling oral calcium supplementation should be an efficient regimen to shift the calcium source from bone to diet, thereby slowing lactation-induced osteopenia. Our results showed that 30-min suckling markedly stimulated maternal duodenal calcium transport, which returned to the baseline at 45 min. Lactating rats given 4 mg/kg per dose calcium via a gavage tube at 90 min pre-suckling 4 doses a day for 14 days prevented a decrease in bone mineral density (BMD) of long bones and vertebrae. On the other hand, a single-dose supplementation, despite the same amount of calcium per day, appeared less effective. Because glucose and galactose further stimulated duodenal calcium transport in lactating rats, pre-suckling calcium supplement containing both sugars successfully normalized plasma ionized calcium and led to better bone gain than that with calcium alone. A histomorphometric study revealed that lactating rats given pre-suckling calcium plus monosaccharide supplement manifested greater trabecular bone volume and thickness and exhibited less eroded surface than in vehicle-treated lactating rats. Beneficial effects of the 14-day calcium supplementation persisted until 6 mo postweaning in dams and also elevated the baseline BMD of the offspring. In conclusion, our proof-of-concept study has corroborated that pre-suckling calcium supplements, especially regimens containing monosaccharides, are efficient in preventing osteopenia in lactating rats and could increase bone density in both breastfeeding mothers and neonates.

-Previously, ␤-thalassemia, an inherited anemic disorder with iron overload caused by loss-of-function mutation of ␤-globin gene, has been reported to induce osteopenia and impaired whole body calcium metabolism, but the pathogenesis of aberrant calcium homeostasis remains elusive. Herein, we investigated how ␤-thalassemia impaired intestinal calcium absorption and whether it could be restored by administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or hepcidin, the latter of which was the liver-derived antagonist of intestinal iron absorption. The results showed that, in hemizygous ␤-globin knockout (BKO) mice, the duodenal calcium transport was lower than that in wild-type littermates, and severity was especially pronounced in female mice. Both active and passive duodenal calcium fluxes in BKO mice were found to be less than those in normal mice. This impaired calcium transport could be restored by 7-day 1,25(OH)2D3 treatment. The 1,25(OH)2D3-induced calcium transport was diminished by inhibitors of calcium transporters, e.g., L-type calcium channel, NCX1, and PMCA1b, as well as vesicular transport inhibitors. Interestingly, the duodenal calcium transport exhibited an inverse correlation with transepithelial iron transport, which was markedly enhanced in thalassemic mice. Thus, 3-day subcutaneous hepcidin injection and acute direct hepcidin exposure in the Ussing chamber were capable of restoring the thalassemia-associated impairment of calcium transport; however, the positive effect of hepcidin on calcium transport was completely blocked by proteasome inhibitors MG132 and bortezomib. In conclusion, both 1,25(OH)2D3 and hepcidin could be used to alleviate the ␤-thalassemia-associated impairment of calcium absorption. Therefore, our study has shed light on the development of a treatment strategy to rescue calcium dysregulation in ␤-thalassemia.

Background The reported association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme ( ACE ) gene and the risk for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains controversial despite the publication of four meta-analyses on this topic. Here, we updated the meta-analysis with more studies and additional assessments that include adults and children within the context of the coronavirus disease 2019 (COVID-19) pandemic. Methods Sixteen articles (22 studies) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using three genetic models (allele, recessive and dominant), in which ARDS patients were compared with non-ARDS patients (A1) and healthy controls (A2). Mortality outcomes were also assessed (A3). The influence of covariates was examined by meta-regression. Bonferroni correction was performed for multiple pooled associations. Subgroup analyses based on ethnicity (Asians, Caucasians) and life stage (adults, children) were conducted. Heterogeneity was addressed with outlier treatment. Results This meta-analysis generated 68 comparisons, 21 of which were significant. Of the 21, four A1 and three A3 highly significant (P a = 0.00001–0.0008) outcomes withstood Bonferroni correction. For A1, allele and recessive associations were found in overall (OR 0.49, 95% CI 0.39–0.61), Caucasians (OR 0.46, 95% CI 0.35–0.61) and children (ORs 0.49–0.66, 95% CI 0.33–0.84) analyses. For A3, associations were found in overall (dominant: OR 0.45, 95% CI 0.29–0.68) and Asian subgroup (allele/ dominant: ORs 0.31–0.39, 95% CIs 0.18–0.63) analyses. These outcomes were either robust, or statistically powered or both and uninfluenced by covariates. Conclusions Significant associations of the ACE I/D polymorphism with the risk of ALI/ARDS were indicated in Caucasians and children as well as in Asians in mortality analysis. These findings were underpinned by high significance, high statistical power and robustness. ACE genotypes may be useful for ALI/ARDS therapy for patients with COVID-19.

Fibroblast growth factor (FGF)-21 is a potent endocrine factor that improves insulin resistance and obesity-associated metabolic disorders. However, concomitant activation of peroxisome proliferator-activated receptor-γ by FGF-21 makes bone susceptible to osteopenia and fragility fracture. Since an increase in body weight often induced adaptive change in bone by making it resistant to fracture, it was unclear whether FGF-21 would still induce bone defects in overweight rats. Therefore, the present study aimed to investigate bone microstructure and its mechanical properties in high fat diet (HF)-fed rats treated with 0.1 mg/kg/day FGF-21. Eighteen male rats were divided into two groups to receive either a normal diet or HF for 12 weeks. HF rats were then divided into two subgroups to receive either vehicle or FGF-21 for 4 weeks. The results showed that HF led to obesity, dyslipidemia and insulin resistance, as indicated by hyperinsulinemia with euglycemia. In HF rats, there was an increase in tibial yield displacement (an indicator of ability to be deformed without losing toughness, as determined by 3-point bending) without changes in tibial trabecular volumetric bone mineral density (vBMD) or cortical bone parameters, e.g., cortical thickness and bone area. FGF-21 treatment strongly improved the metabolic parameters and increased insulin sensitivity in HF rats. However, FGF-21-treated HF rats showed lower yield displacement, trabecular vBMD, trabecular bone volume, trabecular thickness, and osteoblast surface compared with vehicle-treated HF rats. These findings suggest that, despite being a potent antagonist of insulin resistance and visceral fat accumulation, FGF-21 is associated with bone defects in HF rats.