1,25(OH)2D通过FGF23/Klotho/TRPV5轴在老年骨质疏松高尿钙流失及骨矿化障碍发生中的作用及机制研究

老年骨质疏松患者尿钙增加，对骨矿化产生不利影响，但详细机制不明。新近发现FGF23为钙保护激素。TRPV5是肾脏钙重吸收的关键蛋白，受1,25(OH)2D和成骨细胞分泌的FGF23调控。课题组证实，老年骨质疏松小鼠1,25(OH)2D、FGF23水平和肾脏TRPV5的表达降低。推测老年骨质疏松患者尿钙增加可能是由于体内维生素D水平下降，进而引起成骨细胞FGF23分泌减少，导致肾脏TRPV5表达下降和钙重吸收障碍。本研究选用VDR、Fgf23基因敲除等多种老年鼠模型，结合体外成骨细胞、肾小管上皮细胞培养，以期在整体、系统和细胞分子水平明确老年骨质疏松患者维生素D缺乏导致肾脏钙重吸收障碍和高尿钙流失，影响骨正常矿化的病理生理机制，阐明FGF23/Klotho轴介导的1,25(OH)2D缺乏下调肾脏TRPV5表达的分子机制，进一步揭示老年骨质疏松症的发病机制，为骨质疏松的防治提供新的理论。

The pathogenetic mechanism underlying osteoporosis is complex and there is lack of effective prevention and treatment of this disorder. It is well documented that elderly patients with osteoporosis have high incidence of hypercalciuria. However, the mechanism of hypercalciruia in patients with osteoporosis is not well established. Calcium reabsorption in the distal renal tubule involves an active transcellular mechanism, in which calcium uptake by TRPV5 is a rate-limiting and key step. Studies indicated that the expression of TRPV5 is regulated by 1,25(OH)2D as well as FGF23 which is secreted by bone and target at kidney, however, the exact mechanism is stilled need to be clarified. We have previous found senile osteoporosis mouse with low serum 1,25(OH)2D level, low serum FGF23 level and reduced renal TRPV5 expression. We therefore hypothesized that low vitamin D play an important role in hypercalciuria in senile osteoporosis. Vitamin D deficiency can affect normal expression of FGF23 in bone, further down-regulate TRPV5 expression and reduce renal calcium reabsorption. Here in the current project, we plan to employ VDR knockout aging mice model, Fgf23 knockout aging mice model and osteoblasts culture, renal tubular epithelial cell culture, through targeted in vivo and in vitro studies, to investigate whether 1,25(OH)2D deficiency down regulate renal TRPV5 expression through FGF23/Klotho signaling, lead to defect renal calcium reabsorption and impaired bone mineralization in senile osteoporosis and the molecular mechanism involved. This study will help to reveal the role of vitamin D in age-related bone loss and senile osteoporosis and may present a novel strategy for prevention and therapy of osteoporosis.