Lv Yun-Gang, Kang Li, Wu Guangyao
Department of Magnetic Resonance Imaging, Zhongnan Hospital, Wuhan University, No. 185 Donghu Road, Wuhan 430071, PR China.
Department of Interventional Radiology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia 010017, PR China.
Biochem Biophys Res Commun. 2016 Oct 14;479(2):372-379. doi: 10.1016/j.bbrc.2016.09.083. Epub 2016 Sep 17.
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.
绝经后女性的雌激素缺乏常常会激活破骨细胞（OC），加速骨质吸收，并导致骨质疏松症（OP）。先前的研究表明，干扰素γ（IFNγ）可增加骨质吸收，可能参与绝经后骨质疏松症的发病过程。氟中毒也会增加骨折风险和氟斑牙，并且氟化物可能会增强绝经后女性破骨细胞的形成并诱导破骨细胞性骨破坏，但其潜在机制尚不清楚。在此，我们发现，居住在氟中毒地区的绝经后女性血清氟化物和IFNγ水平与骨密度（BMD）呈负相关。雌激素可抑制IFNγ，而氟化物会使IFNγ升高，在雌激素缺乏的情况下，IFNγ在引发骨质流失中起关键作用。在体外，雌激素处理可抑制Raw264.7细胞（一种破骨细胞祖细胞系）中的IFNγ，而氟化物则可使其增加。在卵巢切除（Ovx）小鼠中，雌激素缺乏和IFNγ会促进体内破骨细胞的激活及随后的骨质流失。然而，IFNγ缺乏可防止Ovx小鼠即使在氟化物存在的情况下发生骨质流失。有趣的是，在雌激素受体α（ERα）缺乏的情况下，氟化物不会增加IFNγ的表达，但在雌激素受体β（ERβ）缺乏的情况下则会增加。这些发现表明，氟中毒通过依赖IFNγ的机制增加绝经后骨质疏松症的骨质流失。IFNγ信号激活破骨细胞并加重雌激素缺乏，从而诱发骨质疏松症。因此，刺激IFNγ的产生是氟化物促进骨质流失的关键“上游”机制。抑制IFNγ水平可能构成预防骨质流失的一种治疗方法。
