Fluoride-induced osteoporosis via interfering with the RANKL/RANK/OPG pathway in ovariectomized rats: Oophorectomy shifted skeletal fluorosis from osteosclerosis to osteoporosis

Ye Jin; Bian-Hua Zhou; Jing Zhao; Mohammad Mehdi Ommati; Shuai Wang; Hong-Wei Wang

doi:10.1016/j.envpol.2023.122407

Fluoride-induced osteoporosis via interfering with the RANKL/RANK/OPG pathway in ovariectomized rats: Oophorectomy shifted skeletal fluorosis from osteosclerosis to osteoporosis

Environ Pollut. 2023 Nov 1:336:122407. doi: 10.1016/j.envpol.2023.122407. Epub 2023 Aug 17.

Authors

Ye Jin¹, Bian-Hua Zhou², Jing Zhao³, Mohammad Mehdi Ommati⁴, Shuai Wang⁵, Hong-Wei Wang⁶

Affiliations

¹ Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Luoyang, 471000, Henan, People's Republic of China. Electronic address: jinye@stu.haust.edu.cn.
² Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Luoyang, 471000, Henan, People's Republic of China. Electronic address: zhoubh@haust.edu.cn.
³ Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Luoyang, 471000, Henan, People's Republic of China. Electronic address: zhaojing19901230@126.com.
⁴ Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Luoyang, 471000, Henan, People's Republic of China. Electronic address: mehdi_ommati@outlook.com.
⁵ Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Luoyang, 471000, Henan, People's Republic of China. Electronic address: wang525shuai@163.com.
⁶ Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Luoyang, 471000, Henan, People's Republic of China. Electronic address: wanghw@haust.edu.cn.

PMID: 37597730
DOI: 10.1016/j.envpol.2023.122407

Abstract

Osteosclerosis and osteoporosis are the two main clinical manifestations of skeletal fluorosis. However, the reasons for the different clinical manifestations are unclear. In this study, we established the fluoride (F) -exposed ovariectomized (OVX) and non-OVX rat models to assess the potential role of ovarian function loss in osteosclerosis and osteoporosis. Micro-CT scanning showed that excessive F significantly induced a high bone mass in non-OVX rats. In contrast, a low bone mass manifestation was presented in OVX F-exposed rats. Also, a prominent feature of increasing trabecular connectivity, collagen area, growth plate thickness, and reduced trabecular space was found by histopathological morphology in non-OVX F-exposed rats; an opposite result was observed in OVX F-exposed. These alterations indicated ovariectomy was a vital factor leading to osteosclerosis or osteoporosis in skeletal fluorosis. Furthermore, levels of bone alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase (TRAP) increased, combined with the increasing osteoclasts number, showing a sign of high bone turnover in both OVX and non-OVX F-exposed rats. Mechanistically, oophorectomy considerably activated the RANKL/RANK/OPG signaling pathway. Meanwhile, it was discovered that upregulated NF-κB positively facilitated the accumulation of nuclear factor of activated T-cells 1 (NFATC1), significantly promoting osteoclast differentiation. To sum up, this study greatly enriched the causes of clinical skeletal fluorosis and provided a new perspective for studying the pathogenesis of skeletal fluorosis.

Keywords: Fluorosis; Micro-CT; Oophorectomy; Osteoclast; RANK; Skeletal fluorosis.