Fluorosis increases the risk of postmenopausal osteoporosis by stimulating interferon γ

Biochem Biophys Res Commun. 2016 Oct 14;479(2):372-379. doi: 10.1016/j.bbrc.2016.09.083. Epub 2016 Sep 17.

Abstract

Estrogen deficiency in postmenopausal women frequently activates osteoclasts (OC), accelerates bone resorption, and leads to osteoporosis (OP). Previous studies have demonstrated that interferon γ (IFNγ) could increase bone resorption and may be involved in postmenopausal OP. Fluorosis also increased the risk of fractures and dental fluorosis, and fluoride may enhance osteoclast formation and induce osteoclastic bone destruction in postmenopausal women, but the underlying mechanisms are as yet unknown. Here, we show that serum fluoride and IFNγ levels are negatively correlated with bone mineral density (BMD) in postmenopausal women residing in a fluorotic area. Estrogen suppresses IFNγ, which is elevated by fluoride, playing a pivotal role in triggering bone loss in estrogen-deficient conditions. In vitro, IFNγ is inhibited by estrogen treatment and increased by fluoride in Raw264.7 cell, an osteoclast progenitor cell line. In ovariectomized (Ovx) mice, estrogen loss and IFNγ promote OC activation and subsequent bone loss in vivo. However, IFNγ deficiency prevents bone loss in Ovx mice even in fluoride conditions. Interestingly, fluoride fails to increase IFNγ expression in estrogen receptor α (ERα)-deficient conditions, but not in ERβ-deficient conditions. These findings demonstrate that fluorosis increases the bone loss in postmenopausal OP through an IFNγ-dependent mechanism. IFNγ signaling activates OC and aggravates estrogen deficiency inducing OP. Thus, stimulation of IFNγ production is a pivotal ''upstream'' mechanism by which fluoride promotes bone loss. Suppression of IFNγ levels may constitute a therapeutic approach for preventing bone loss.

Keywords: Fluorosis; Interferon γ; Osteoporosis; Postmenopausal.

MeSH terms

  • Aged
  • Animals
  • Bone Density
  • Bone Resorption
  • CD4-Positive T-Lymphocytes / cytology
  • Estrogen Receptor beta / metabolism
  • Estrogens / deficiency
  • Estrogens / metabolism
  • Female
  • Fluorides / chemistry
  • Fluorosis, Dental / complications
  • Fluorosis, Dental / metabolism*
  • Gene Silencing
  • Humans
  • Interferon-gamma / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Osteoclasts / cytology
  • Osteoclasts / metabolism
  • Osteoporosis
  • Osteoporosis, Postmenopausal / complications
  • Osteoporosis, Postmenopausal / metabolism*
  • Signal Transduction
  • Stem Cells / cytology
  • X-Ray Microtomography

Substances

  • Estrogen Receptor beta
  • Estrogens
  • Interferon-gamma
  • Fluorides