Abstract：
Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN remodeling. In osteoclasts, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) is critical for stimulating bone resorption. Since osteocytes also resorb matrix, we hypothesize that NFATc1 plays a role in 1,25D and phosphate-mediated LCN remodeling. Consistent with this, 1,25D and phosphate suppress Nfatc1 mRNA expression in IDG-SW3 osteocytes, and knockdown of Nfatc1 expression in IDG-SW3 cells blocks 1,25D- and phosphate-mediated suppression of matrix resorption gene expression and 1,25D- and phosphate-mediated suppression of RANKL-induced acidification of the osteocyte microenvironment. To determine the role of NFATc1 in 1,25D- and phosphate-mediated LCN remodeling in vivo, histomorphometric analyses of tibiae from mice lacking osteocyte-specific Nfatc1 in Vdrf/f;Dmp1Cre+ and Npt2aKO mice were performed, demonstrating that bones from these mice have decreased lacunar size and expression of matrix resorption genes, and improved canalicular structure compared to Vdrf/f;Dmp1Cre+ and Npt2aKO control. This study demonstrates that NFATc1 is necessary for 1,25D- and phosphate-mediated regulation of LCN remodeling.
摘要：
骨细胞嵌入腔隙中并通过小管连接（腔隙-小管网络，LCN）。X连锁低磷酸盐血症（Hyp）小鼠的骨骼，1,25二羟维生素D（1,25D）和低磷酸盐血症的产生受损，具有异常的LCN结构，通过用1,25D或抗FGF23靶向抗体治疗而得到改善，1,25D和磷酸盐在调节LCN重塑中的支持作用。骨细胞中缺乏维生素D受体（VDR）的小鼠（Vdrf/f;Dmp1Cre）和缺乏磷酸钠转运蛋白2a（Npt2aKO）的小鼠的骨骼，血清磷酸盐低，血清1,25D高，损害了LCN组织，证明1,25D和低磷血症的骨细胞特异性作用调节LCN重塑。在破骨细胞中，活化T细胞胞浆核因子1(NFATc1)对刺激骨吸收至关重要。因为骨细胞也吸收基质，我们假设NFATc1在1,25D和磷酸盐介导的LCN重塑中起作用。与此一致，1,25D和磷酸盐抑制IDG-SW3骨细胞中Nfatc1mRNA的表达，IDG-SW3细胞中Nfatc1表达的敲低可阻断1,25D和磷酸盐介导的基质吸收基因表达的抑制，以及1,25D和磷酸盐介导的RANKL诱导的骨细胞微环境酸化的抑制。为了确定NFATc1在1,25D和磷酸盐介导的LCN体内重塑中的作用，在Vdrf/f中缺乏骨细胞特异性Nfatc1的小鼠的胫骨的组织形态计量学分析；进行Dmp1Cre和Npt2aKO小鼠，证明这些小鼠的骨骼减少了腔隙大小和基质吸收基因的表达，与Vdrf/f；Dmp1Cre和Npt2aKO对照相比，小管结构得到了改善。这项研究表明，NFATc1对于1,25D和磷酸盐介导的LCN重塑调节是必需的。
