title: Fluorosis increases the risk of postmenopausal osteoporosis by stimulating interferon γ.
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.
authors.affiliation: Department of Magnetic Resonance Imaging, Zhongnan Hospital, Wuhan University, No. 185 Donghu Road, Wuhan 430071, PR China. Electronic address: yunganglv@126.com.
authors.forename: Yun-Gang
authors.initials: YG
authors.lastname: Lv
authors.affiliation: Department of Interventional Radiology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia 010017, PR China. Electronic address: 30417395@qq.com.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Magnetic Resonance Imaging, Zhongnan Hospital, Wuhan University, No. 185 Donghu Road, Wuhan 430071, PR China. Electronic address: wugy1974@yeah.net.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Wu
mesh_terms: D000368:Aged; D000818:Animals; D015519:Bone Density; D001862:Bone Resorption; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism; D005260:Female; D005459:Fluorides / Q000737:chemistry; D009050:Fluorosis, Dental / Q000150:complications / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010024:Osteoporosis; D015663:Osteoporosis, Postmenopausal / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D055114:X-Ray Microtomography
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D007371:Interferon-gamma; D005459:Fluorides
keywords: Fluorosis; Interferon γ; Osteoporosis; Postmenopausal