Vitamin D - Molecular mechanism of action
Vitamin D - Molecular mechanism of action
复制标题
DOI：
10.1196/annals.1402.070
复制
发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Joshi, Sneha
中科院分区：
文献类型：
--
作者：
Christakos, Sylvia;Dhawan, Puneet;Joshi, Sneha
维生素D维持钙平衡，是骨骼发育和维护所必需的。最近的证据表明，维生素D与骨骼以外的健康之间存在相互关系，包括对细胞增殖和免疫系统的影响。我们实验室在目标蛋白的功能和调节方面的新进展为维生素D的作用机制提供了新的见解。我们实验室的研究表明，钙结合蛋白Calbindin被报道为钙扩散的促进剂，在不同组织中也具有防止细胞凋亡的重要作用，包括保护成骨细胞和胰岛β细胞免受细胞因子的破坏。这些发现对包括糖尿病和骨质疏松症在内的许多疾病的治疗干预具有重要意义。本实验室最近利用Calbindin-D-9k缺失突变小鼠以及缺乏1，25(OH)(2)D-3(1，25(OH)(2)D-3)诱导的上皮细胞钙通道TRPV6的小鼠进行的肠道钙吸收研究，首次为Calbindin-D-9k和TRPV6独立调节主动钙吸收提供了证据。除钙结合蛋白外，1，25(OH)(2)D-3在肠道和肾脏的另一个主要靶点是25(OH)D-3 24羟基酶(24(OH)ase)，该酶参与1，25(OH)(2)D-3的分解代谢。在我们的实验室中，我们已经确定了与维生素D受体协同调节24(OH)酶表达的各种因素，包括C/EBPβ、SWI/SNF(利用ATP水解能重塑染色质的复合体)以及甲基转移酶CARM1和G9a。也有证据表明C/EBPβ是一种核偶联因子，它协调1，25(OH)(2)D-3和甲状旁腺素对骨桥蛋白的调节。我们的发现定义了新的机制，这些机制可能对理解1，25(OH)(2)D-3如何介导其多种生物学效应具有重要意义。
Vitamin D maintains calcium homeostasis and is required for bone development and maintenance. Recent evidence has indicated an interrelationship between vitamin D and health beyond bone, including effects on cell proliferation and on the immune system. New developments in our lab related to the function and regulation of target proteins have provided novel insights into the mechanisms of vitamin D action. Studies in our lab have shown that the calcium-binding protein, calbindin, which has been reported to be a facilitator of calcium diffusion, also has an important role in protecting against apoptotic cell death in different tissues including protection against cytokine destruction of osteoblastic and pancreatic beta cells. These findings have important implications for the therapeutic intervention of many disorders including diabetes and osteoporosis. Recent studies in our laboratory of intestinal calcium absorption using calbindin-D-9k null mutant mice as well as mice lacking the 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) inducible epithelial calcium channel, TRPV6, provide evidence for the first time of calbindin-D-9k and TRPV6 independent regulation of active calcium absorption. Besides calbindin, the other major target of 1,25(OH)(2)D-3 in intestine and kidney is 25(OH)D-3 24 hydroxylase (24(OH)ase), which is involved in the catabolism of 1,25(OH)(2)D-3. In our laboratory we have identified various factors that cooperate with the vitamin D receptor in regulating 24(OH)ase expression including C/EBP beta, SWI/SNF (complexes that remodel chromatin using the energy of ATP hydrolysis) and the methyltransferases, CARM1 and G9a. Evidence is also presented for C/EBP beta as a nuclear coupling factor that coordinates regulation of osteopontin by 1,25(OH)(2)D-3 and PTH. Our findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)(2)D-3 mediates its multiple biological effects.