The pathogenesis of endemic fluorosis: Research progress in the last 5 years

Abstract

Fluorine is one of the trace elements necessary for health. It has many physiological functions, and participates in normal metabolism. However, fluorine has paradoxical effects on the body. Many studies have shown that tissues and organs of humans and animals appear to suffer different degrees of damage after long-term direct or indirect exposure to more fluoride than required to meet the physiological demand. Although the aetiology of endemic fluorosis is clear, its specific pathogenesis is inconclusive. In the past 5 years, many researchers have conducted in-depth studies into the pathogenesis of endemic fluorosis. Research in the areas of fluoride-induced stress pathways, signalling pathways and apoptosis has provided further extensive knowledge at the molecular and genetic level. In this article, we summarize the main results.

Keywords: apoptosis; fluoride; pathogenesis; research progress; signalling pathways.

Figure 1

The key words for pathogenesis of endemic fluorosis in the last 5 years. From the perspective of the effects of fluoride on different tissues and organs of the body, research work from the last five years has mainly focused on effects at the molecular and genetic levels, such as fluoride‐induced stress pathways, signalling pathways and apoptosis

Figure 2

Common alterations in fluorosis‐apoptosis. Caspases, a family of cysteine proteases, are the central regulators of apoptosis. FasL can activate initiator caspases (Pro‐caspase 8 and 10), then cleave and activate the effector caspases 3, 6 and 7, leading to apoptosis. Fluoride exposure can activate these signalling pathways and induce apoptosis. In addition, excessive fluoride induces stress pathways such as oxidative stress and endoplasmic reticulum stress, thus promoting apoptosis. Many signalling pathways such as Erk1/2 and PI3K/Akt induce anti‐apoptotic Bcl‐2 family members. These Bcl‐2 family members protect the integrity of mitochondria, preventing Cytochrome C release and the subsequent activation of caspase‐9. TNF‐α may activate both pro‐apoptotic and anti‐apoptotic pathways. TNF‐α can induce apoptosis by activating caspase 8 and 10, but can also inhibit apoptosis via NF‐κB. Fluoride exposure can inhibit these survival signalling pathways

Figure 3

Common alterations in fluorosis‐proliferation and differentiation. The role of fluoride in cell proliferation and differentiation is the focus of research into the pathogenesis of skeletal fluorosis. The BMP/Smad and Wnt signalling pathways play important roles in the viability and differentiation of osteoblasts. TGFβ receptor 1‐smad3 signalling participates in the mechanism of biphasic modulation of osteoclast mode, regulated by fluoride. In addition, the FGF signalling pathway, which activates Akt and Erk1/2pathways, is responsible for the balance between cell proliferation and differentiation

Figure 4

Common alterations in fluorosis‐homeostasis & autophagy. (a) NO is an important cellular signalling molecule. It helps modulate vascular tone, insulin secretion, airway tone and peristalsis, and is involved in angiogenesis and neural development. The PI3K/AKT/eNOS pathway plays a crucial role in homeostasis. Excessive fluoride exposure causes reduced expression of NO, which leads to damage of tissues and organs. (b) The kinase mTOR is a critical regulator of autophagy induction, with activated mTOR (PI3K‐1/Akt and MAPK/Erk1/2 signalling) suppressing autophagy. Fluoride can inhibit these pathways, so may lead to the development of autophagy. Besides, excessive fluoride exposure activates SIRT1/autophagy via JNK signalling