20S-Hydroxyvitamin D3, Noncalcemic Product of CYP11A1 Action on Vitamin D3, Exhibits Potent Antifibrogenic Activity in Vivo
20S-Hydroxyvitamin D3, Noncalcemic Product of CYP11A1 Action on Vitamin D3, Exhibits Potent Antifibrogenic Activity in Vivo
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DOI：
10.1210/jc.2012-3074
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发表时间：
2013-02-01
影响因子：
5.8
通讯作者：
Postlethwaite, Arnold E.
中科院分区：
文献类型：
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作者：
Slominski, Andrzej;Janjetovic, Zorica;Postlethwaite, Arnold E.
背景：系统性硬化症和相关纤维化疾病没有有效的治疗方法。最近，CYP11A1 对维生素 D-3 的作用被证明可产生具有生物活性的 20S-羟基维生素 D [20(OH)D-3] 和 20,23(OH)(2)D-3、20,22(OH)(2)D-3 和 17,20,23(OH)(3)D-3。 目的：因为 20(OH)D-3 是非钙血症的在非常高的剂量下（无毒）体内，我们评估了其体外和体内的抗纤维形成活性。由于其进一步被CYP11A1代谢，我们还测试了其羟基衍生物，特别是20,23(OH)(2)D-3的临床前效用。设计：使用来自硬皮病和正常供体的人真皮成纤维细胞来测试羟基维生素D衍生物抑制TGF-β1诱导的胶原和透明质酸合成以及抑制细胞增殖的效率。使用博来霉素诱导的 C57BL/6 小鼠硬化测试了 20(OH)D-3 的体内活性。结果：在培养的人成纤维细胞中，20(OH)D-3 和 20,23(OH)(2)D-3 与 1,25(OH)(2)D-3 类似，可抑制 TGF-β 1 诱导的胶原和透明质酸合成。此外，20(OH)D-3、20,23(OH)(2)D-3 和 1,25(OH)(2)D-3 抑制 TGF-β 1 诱导的 COL1A2、COL3A1 和透明质酸合成酶 2 mRNA 的表达，表明它们在转录水平调节这些基质成分。 20(OH) D3、20,23(OH)(2)D-3、20,22(OH)(2)D-3 和 17,20,23(OH)(3)D-3 抑制真皮成纤维细胞的增殖，其效力与 1,25(OH)(2)D-3 相当，其中 20(OH)D-2 活性较低，1 α(OH)D-3 几乎没有活性。不活跃。 3μg/kg的20,23(OH)(2)D-3对血清Ca++或成纤维细胞生长因子23水平没有影响，并且不会引起任何明显的发病迹象。总胶原蛋白含量以及皮肤活检的苏木精和伊红染色证明，20(OH)D-3 显着抑制了接受 sc 博来霉素的小鼠的纤维形成。结论：20(OH)D-3 是硬皮病临床前研究的极好候选者，其代谢的其他 CYP11A1 衍生产物值得进一步测试抗纤维原活性。 （临床内分泌代谢杂志 98：E298-E303，2013 年）
Context: There is no effective treatment for systemic sclerosis and related fibrosing diseases. Recently the action of CYP11A1 on vitamin D-3 was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D-3] and 20,23(OH)(2)D-3, 20,22(OH)(2)D-3, and 17,20,23(OH)(3)D-3.Objectives: Because 20(OH)D-3 is noncalcemic (nontoxic) in vivo at very high doses, we evaluated its antifibrogenic activities both in vitro and in vivo. Because it is further metabolized by CYP11A1, we also tested preclinical utilities of its hydroxyderivatives, especially 20,23(OH)(2)D-3.Design: Human dermal fibroblasts from scleroderma and normal donors were used to test the efficiency of hydroxyvitamin D derivatives in inhibiting TGF-beta 1-induced collagen and hyaluronan synthesis and inhibiting cell proliferation. The in vivo activity of 20(OH)D-3 was tested using bleomycin-induced sclerosis in C57BL/6 mice.Results: 20(OH)D-3 and 20,23(OH)(2)D-3 inhibited TGF-beta 1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)(2)D-3 in cultured human fibroblasts. Also, 20(OH)D-3, 20,23(OH)(2)D-3, and 1,25(OH)(2)D-3 suppressed TGF-beta 1-induced expression of COL1A2, COL3A1, and hyaluronan synthase-2 mRNA, indicating that they regulate these matrix components at the transcriptional level. 20(OH) D3, 20,23(OH)(2)D-3, 20,22(OH)(2)D-3, and 17,20,23(OH)(3)D-3 inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)(2)D-3, with 20(OH)D-2 being less active and 1 alpha(OH)D-3 being almost inactive. 20,23(OH)(2)D-3 at 3 mu g/kg had no effect on serum Ca++ or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D-3 markedly suppressed fibrogenesis in mice given sc bleomycin as demonstrated by total collagen content and hematoxylin and eosin staining of skin biopsies.Conclusions: 20(OH)D-3 is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity. (J Clin Endocrinol Metab 98: E298-E303, 2013)