1,25-Dihydroxyvitamin D3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells

Sunil Krishna Halder, Kevin G. Osteen, Ayman Al-Hendy

Research output: Contribution to journalArticle

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Abstract

Uterine fibroids (leiomyomas) are the most common benign tumors associated with excessive deposition of extracellular matrix (ECM)-associated proteins that increase fibroid tumorigenicity. Herein, we determined the expression levels of vitamin D receptor (VDR) protein in human uterine fibroids and compared these levels to those in adjacent normal myometrium. Using Western blot analysis, we found that more than 60% of uterine fibroids analyzed (25 of 40) expressed low levels of VDR. We also found that the biologically active 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), which functions via binding to its nuclear VDR, induced VDR in a concentration-dependent manner and reduced ECM-associated fibrotic and proteoglycans expression in immortalized human uterine fibroid cell line (HuLM). At 1-10 nM concentrations, 1,25(OH)2D3 significantly induced (P , 0.05) nuclear VDR, which was further stimulated by higher concentrations of 1,25(OH)2D3 in HuLM cells. 1,25(OH)2D3 at 10 nM also significantly reduced (P<0.05) the protein expression of ECM-associated collagen type 1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) in HuLM cells. We also found that 1,25(OH)2D3 reduced mRNA and protein expressions of proteoglycans such as fibromodulin, biglycan, and versican in HuLM cells. Moreover, the aberrant expression of structural smooth muscle actin fibers was reduced by 1,25(OH)2D3 treatment in a concentration-dependent manner in HuLM cells. Taken together, our results suggest that human uterine fibroids express reduced levels of VDR compared to the adjacent normal myometrium and that treatment with 1,25(OH)2D3 can potentially reduce the aberrant expression of major ECM-associated proteins in HuLM cells. Thus, 1,25(OH)2D3 might be an effective, safe, nonsurgical treatment option for human uterine fibroids.

Original languageEnglish (US)
Article number150
JournalBiology of Reproduction
Volume89
Issue number6
DOIs
StatePublished - Jan 1 2013

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Calcitriol
Extracellular Matrix Proteins
Leiomyoma
Calcitriol Receptors
Myometrium
Proteoglycans
Versicans
Biglycan
Plasminogen Activator Inhibitor 1
Collagen Type I
Fibronectins
Extracellular Matrix
Smooth Muscle
Actins
Proteins
Western Blotting
Cell Line
Messenger RNA

Keywords

  • Extracellular matrix (ECM)
  • Fibroids
  • Vitamin d receptor (VDR)

ASJC Scopus subject areas

  • Cell Biology

Cite this

1,25-Dihydroxyvitamin D3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells. / Halder, Sunil Krishna; Osteen, Kevin G.; Al-Hendy, Ayman.

In: Biology of Reproduction, Vol. 89, No. 6, 150, 01.01.2013.

Research output: Contribution to journalArticle

Halder, Sunil Krishna ; Osteen, Kevin G. ; Al-Hendy, Ayman. / 1,25-Dihydroxyvitamin D3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells. In: Biology of Reproduction. 2013 ; Vol. 89, No. 6.
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AB - Uterine fibroids (leiomyomas) are the most common benign tumors associated with excessive deposition of extracellular matrix (ECM)-associated proteins that increase fibroid tumorigenicity. Herein, we determined the expression levels of vitamin D receptor (VDR) protein in human uterine fibroids and compared these levels to those in adjacent normal myometrium. Using Western blot analysis, we found that more than 60% of uterine fibroids analyzed (25 of 40) expressed low levels of VDR. We also found that the biologically active 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), which functions via binding to its nuclear VDR, induced VDR in a concentration-dependent manner and reduced ECM-associated fibrotic and proteoglycans expression in immortalized human uterine fibroid cell line (HuLM). At 1-10 nM concentrations, 1,25(OH)2D3 significantly induced (P , 0.05) nuclear VDR, which was further stimulated by higher concentrations of 1,25(OH)2D3 in HuLM cells. 1,25(OH)2D3 at 10 nM also significantly reduced (P<0.05) the protein expression of ECM-associated collagen type 1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) in HuLM cells. We also found that 1,25(OH)2D3 reduced mRNA and protein expressions of proteoglycans such as fibromodulin, biglycan, and versican in HuLM cells. Moreover, the aberrant expression of structural smooth muscle actin fibers was reduced by 1,25(OH)2D3 treatment in a concentration-dependent manner in HuLM cells. Taken together, our results suggest that human uterine fibroids express reduced levels of VDR compared to the adjacent normal myometrium and that treatment with 1,25(OH)2D3 can potentially reduce the aberrant expression of major ECM-associated proteins in HuLM cells. Thus, 1,25(OH)2D3 might be an effective, safe, nonsurgical treatment option for human uterine fibroids.

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