20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo.

Abstract

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-β1-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-β1-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-β1-induced expression of COL1A2, COL3A1, and hyaluronan synthase-2 mRNA, indicating that they regulate these matrix components at the transcriptional level. 20(OH)D(3), 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 1α(OH)D(3) being almost inactive. 20,23(OH)(2)D(3) at 3 μg/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.

• Authors: Andrzej Slominski, Zorica Janjetovic, Robert C Tuckey, Minh N Nguyen, Keka G Bhattacharya, Jin Wang, Wei Li, Yan Jiao, Weikuan Gu, Monica Brown, Arnold E Postlethwaite
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 98 Issue 2 Pg. E298-303 (Feb 2013) ISSN: 1945-7197 [Electronic] United States
• PMID: 23295467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 20-hydroxyvitamin D3
• Hyaluronic Acid
• Collagen
• Calcifediol

Topics

• Animals
• Calcifediol (analogs & derivatives, pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Collagen (biosynthesis)
• Disease Models, Animal
• Fibroblasts (cytology, drug effects, metabolism)
• Humans
• Hyaluronic Acid (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Scleroderma, Systemic (metabolism)
• Skin (cytology, drug effects, metabolism)