Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
Kidney Int. 2010 Jul;78(2):140-5. doi: 10.1038/ki.2010.17. Epub 2010 Feb 24.
The secosteroid hormone 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the natural ligand for the vitamin D receptor, a member of the nuclear receptor superfamily. Upon binding of the ligand, the vitamin D receptor heterodimerizes with the retinoid X receptor and binds to vitamin D response elements in the promoter region of target genes to induce/repress their expression. The target genes that have been identified so far are heterogeneous in nature and reflect the great spectrum of biological activities of 1,25(OH)(2)D(3). Within the last two decades, the receptor has been shown to be present not only in classical target tissues such as bone, kidney, and intestine, but also in many other nonclassical tissues, for example, in the immune system (T and B cells, macrophages, and monocytes), in the reproductive system (uterus, testis, ovary, prostate, placenta, and mammary glands), in the endocrine system (pancreas, pituitary, thyroid, and adrenal cortex), in muscles (skeletal, smooth, and heart muscles), and in brain, skin, and liver. Besides the almost universal presence of vitamin D receptors, different cell types (for example, keratinocytes, monocytes, bone, placenta) are capable of metabolizing 25-hydroxyvitamin D(3) to 1,25(OH)(2)D(3) by the enzyme 25(OH)D(3)-1alpha-hydroxylase, encoded by CYP27B1. The combined presence of CYP27B1 and the specific receptor in several tissues introduced the idea of a paracrine/autocrine role for 1,25(OH)(2)D(3). Moreover, it has been demonstrated that 1,25(OH)(2)D(3) can induce differentiation and inhibit proliferation of normal and malignant cells. Moreover, vitamin D deficiency is associated with an increased risk for nearly all major human diseases such as cancer, autoimmune diseases, cardiovascular, and metabolic diseases. In addition to the treatment of bone disorders with 1,25(OH)(2)D(3), these newly discovered functions open perspectives for the use of 1,25(OH)(2)D(3) as an immune modulator (for example, for the treatment of autoimmune diseases or prevention of graft rejection), inhibitor of cell proliferation, and inducer of cell differentiation (cancer).
甾体激素 1α，25-二羟维生素 D（3）（1，25（OH）（2）D（3））是维生素 D 受体的天然配体，维生素 D 受体是核受体超家族的成员。配体结合后，维生素 D 受体与视黄酸 X 受体异二聚化，并结合到靶基因启动子区域的维生素 D 反应元件上，诱导/抑制其表达。迄今为止，已鉴定的靶基因在性质上是异质的，反映了 1，25（OH）（2）D（3）的广泛生物学活性。在过去的二十年中，已经证明受体不仅存在于经典靶组织（如骨骼、肾脏和肠道）中，而且还存在于许多其他非经典组织中，例如免疫系统（T 和 B 细胞、巨噬细胞和单核细胞）、生殖系统（子宫、睾丸、卵巢、前列腺、胎盘和乳腺）、内分泌系统（胰腺、垂体、甲状腺和肾上腺皮质）、肌肉（骨骼、平滑和心脏肌肉）以及大脑、皮肤和肝脏。除了维生素 D 受体的普遍存在外，不同的细胞类型（例如角质形成细胞、单核细胞、骨骼、胎盘）能够通过酶 25-羟维生素 D（3）-1α-羟化酶将 25-羟维生素 D（3）代谢为 1，25（OH）（2）D（3），该酶由 CYP27B1 编码。几种组织中 CYP27B1 和特定受体的共同存在引入了 1，25（OH）（2）D（3）的旁分泌/自分泌作用的概念。此外，已经证明 1，25（OH）（2）D（3）可以诱导正常和恶性细胞的分化和抑制增殖。此外，维生素 D 缺乏与几乎所有主要人类疾病（如癌症、自身免疫性疾病、心血管和代谢疾病）的风险增加有关。除了用 1，25（OH）（2）D（3）治疗骨骼疾病外，这些新发现的功能为将 1，25（OH）（2）D（3）用作免疫调节剂（例如，用于治疗自身免疫性疾病或预防移植物排斥）、细胞增殖抑制剂和细胞分化诱导剂（癌症）开辟了前景。
