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

Andrzej Slominski, Zorica Janjetovic, Robert C. Tuckey, Minh N. Nguyen, Keka G. Bhattacharya, Jin Wang, Wei Li, Yan Jiao, Weikuan Gu, Monica Brown, Arnold Postlethwaite

Research output: Contribution to journalArticle

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Abstract

Context: There is no effective treatment for systemic sclerosis and related fibrosing diseases. Recently the action of CYP11A1 on vitamin D3 was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D3] and 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3. Objectives: Because 20(OH)D3 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)2D3. 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)D3 was tested using bleomycin- induced sclerosis in C57BL/6 mice. Results: 20(OH)D3 and 20,23(OH)2D 3 inhibited TGF-β1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)2D3 in cultured human fibroblasts. Also, 20(OH)D3, 20,23(OH)2D3, and 1,25(OH) 2D3 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)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)2D3, with 20(OH)D2 being less active and 1α(OH)D3 being almost inactive.20,23(OH) 2D3 at 3μg/kg had no effect on serum Ca++ or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D3 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)D3 is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume98
Issue number2
DOIs
StatePublished - Feb 1 2013

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Cholesterol Side-Chain Cleavage Enzyme
Cholecalciferol
Fibroblasts
Hydroxycholecalciferols
Collagen
Bleomycin
Hyaluronic Acid
Skin
20-hydroxyvitamin D3
20,23-dihydroxyvitamin D3
Biopsy
Systemic Scleroderma
Cell proliferation
Sclerosis
Hematoxylin
Eosine Yellowish-(YS)
Inbred C57BL Mouse
Metabolism
Cell Proliferation
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo. / Slominski, Andrzej; Janjetovic, Zorica; Tuckey, Robert C.; Nguyen, Minh N.; Bhattacharya, Keka G.; Wang, Jin; Li, Wei; Jiao, Yan; Gu, Weikuan; Brown, Monica; Postlethwaite, Arnold.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 98, No. 2, 01.02.2013.

Research output: Contribution to journalArticle

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title = "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 D3 was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D3] and 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3. Objectives: Because 20(OH)D3 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)2D3. 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)D3 was tested using bleomycin- induced sclerosis in C57BL/6 mice. Results: 20(OH)D3 and 20,23(OH)2D 3 inhibited TGF-β1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)2D3 in cultured human fibroblasts. Also, 20(OH)D3, 20,23(OH)2D3, and 1,25(OH) 2D3 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)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)2D3, with 20(OH)D2 being less active and 1α(OH)D3 being almost inactive.20,23(OH) 2D3 at 3μg/kg had no effect on serum Ca++ or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D3 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)D3 is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity.",
author = "Andrzej Slominski and Zorica Janjetovic and Tuckey, {Robert C.} and Nguyen, {Minh N.} and Bhattacharya, {Keka G.} and Jin Wang and Wei Li and Yan Jiao and Weikuan Gu and Monica Brown and Arnold Postlethwaite",
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T1 - 20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo

AU - Slominski, Andrzej

AU - Janjetovic, Zorica

AU - Tuckey, Robert C.

AU - Nguyen, Minh N.

AU - Bhattacharya, Keka G.

AU - Wang, Jin

AU - Li, Wei

AU - Jiao, Yan

AU - Gu, Weikuan

AU - Brown, Monica

AU - Postlethwaite, Arnold

PY - 2013/2/1

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N2 - Context: There is no effective treatment for systemic sclerosis and related fibrosing diseases. Recently the action of CYP11A1 on vitamin D3 was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D3] and 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3. Objectives: Because 20(OH)D3 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)2D3. 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)D3 was tested using bleomycin- induced sclerosis in C57BL/6 mice. Results: 20(OH)D3 and 20,23(OH)2D 3 inhibited TGF-β1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)2D3 in cultured human fibroblasts. Also, 20(OH)D3, 20,23(OH)2D3, and 1,25(OH) 2D3 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)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)2D3, with 20(OH)D2 being less active and 1α(OH)D3 being almost inactive.20,23(OH) 2D3 at 3μg/kg had no effect on serum Ca++ or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D3 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)D3 is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity.

AB - Context: There is no effective treatment for systemic sclerosis and related fibrosing diseases. Recently the action of CYP11A1 on vitamin D3 was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D3] and 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3. Objectives: Because 20(OH)D3 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)2D3. 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)D3 was tested using bleomycin- induced sclerosis in C57BL/6 mice. Results: 20(OH)D3 and 20,23(OH)2D 3 inhibited TGF-β1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)2D3 in cultured human fibroblasts. Also, 20(OH)D3, 20,23(OH)2D3, and 1,25(OH) 2D3 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)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)2D3, with 20(OH)D2 being less active and 1α(OH)D3 being almost inactive.20,23(OH) 2D3 at 3μg/kg had no effect on serum Ca++ or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D3 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)D3 is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity.

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