- Fluoride inhibited chondrocyte proliferation.
- Fluoride increased autophagy in ATDC5 cells.
- Fluoride inhibited PI3K/AKT/mTOR signaling pathway.
- Fluoride-induced adverse effects were mediated by PI3K/AKT/mTOR signaling pathway.
Fluorine is an essential trace element for human health. However, excessive fluoride intake causes skeletal fluorosis which affects cartilage development. Fluoride inhibited chondrocyte proliferation which is the initial and critical step of endochondral ossification, but the underlying mechanism has not been clearly illustrated. Mammalian target of rapamycin (mTOR) is an important protein kinase which modulates various cellular processes and is believed to be a central regulator of chondrocyte proliferation and autophagy. In this study, we explored the effect of fluoride on the proliferation and autophagy of chondrocytes and the regulatory role of mTOR signaling pathway. Our results suggested that NaF inhibited the protein expressions of proliferating cell nuclear antigen (PCNA) and pS6 in cultured fetal rat tibias. Furthermore, NaF significantly downregulated the expressions of mTOR signaling pathway-related genes, including PI3K, AKT, mTOR, 4EBP1 and S6K1 in mouse ATDC5 chondrogenic cell line. We also found that NaF increased autophagy in ATDC5 cells. The mRNA and protein levels of autophagy-related genes LC3, Beclin1 and p62 were significantly changed after NaF treatment. Further studies demonstrated that MHY1485, a small-molecular mTOR activator, totally reversed fluoride-induced promotion of autophagy. MHY1485 also recovered the downregulation of proliferative chondrocytes markers Sox9 and Type ? Collagen (Col2a1) induced by fluoride in ATDC5 cells. Taken together, our result demonstrated that fluoride suppressed proliferation and facilitated autophagy via PI3K/AKT/mTOR signaling pathway in chondrogenesis.
*Original abstract online at https://www.sciencedirect.com/science/article/abs/pii/S0009279721002970
Effects of fluoride on the proliferation and activation of osteoblasts by regulating methylation of the DNA repair genes MGMT and MLH1.
Introduction Fluoride can induce the proliferation and activation of osteoblasts, resulting in skeletal fluorosis progression; however, the specific mechanism is unclear. Methods Cell proliferation was examined using the MTT assay. Flow cytometry was performed to detect the cell cycle distribution. Alkaline phosphatase (ALP) was calculated to evaluate bone formation and turnover. Gene methylation
The pathogenesis of endemic fluorosis: Research progress in the last 5 years.
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
Fluoride-induced oxidative stress in three-dimensional culture of OS732 cells and rats.
Exposure to excessive fluoride poses a threat to human health, including increased susceptibility to developing the skeletal fluorosis. Despite its recognized importance as an endemic disease, little is known about how fluoride directly impacts on osteoblasts. We previously reported that fluoride-stimulating monolayer-cultured osteoblast proliferation or inhibiting cell viability depended on
Fluoride induces hypomethylation of BMP2 and activates osteoblasts through the Wnt/B-catenin signaling pathway.
Background: Skeletal fluorosis has become a public health issue in recent years as its serious impact on patients' life expectancy. Bone morphogenetic protein 2 (BMP2) plays a key role in promoting osteogenesis. However, the mechanism of BMP2-Wnt/B-catenin axis in skeletal fluorosis needs further exploration. Methods: The RT-qPCR
Aberrant methylation-induced dysfunction of p16 is associated with osteoblast activation caused by fluoride.
Chronic exposure to fluoride continues to be a public health problem worldwide, affecting thousands of people. Fluoride can cause abnormal proliferation and activation of osteoblast and osteoclast, leading to skeletal fluorosis that can cause pain and harm to joints and bones and even lead to permanent disability. Nevertheless, there is
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Skeletal Fluorosis: The Misdiagnosis Problem
It is a virtual certainty that there are individuals in the general population unknowingly suffering from some form of skeletal fluorosis as a result of a doctor's failure to consider fluoride as a cause of their symptoms. Proof that this is the case can be found in the following case reports of skeletal fluorosis written by doctors in the U.S. and other western countries. As can be seen, a consistent feature of these reports is that fluorosis patients--even those with crippling skeletal fluorosis--are misdiagnosed for years by multiple teams of doctors who routinely fail to consider fluoride as a possible cause of their disease.
Fluoride & Osteoarthritis
While the osteoarthritic effects that occurred from fluoride exposure were once considered to be limited to those with skeletal fluorosis, recent research shows that fluoride can cause osteoarthritis in the absence of traditionally defined fluorosis. Conventional methods used for detecting skeletal fluorosis, therefore, will fail to detect the full range of people suffering from fluoride-induced osteoarthritis.
As demonstrated by the studies below, skeletal fluorosis may produce adverse symptoms, including arthritic pains, clinical osteoarthritis, gastrointestinal disturbances, and bone fragility, before the classic bone change of fluorosis (i.e., osteosclerosis in the spine and pelvis) is detectable by x-ray. Relying on x-rays, therefore, to diagnosis skeletal fluorosis will invariably fail to protect those individuals who are suffering from the pre-skeletal phase of the disease. Moreover, some individuals with clinical skeletal fluorosis will not develop an increase in bone density, let alone osteosclerosis, of the spine. Thus, relying on unusual increases in spinal bone density will under-detect the rate of skeletal fluoride poisoning in a population.
Symposium on the non-skeletal phase of chronic fluorosis: The Joints
Of 300 patients with endemic skeletal fluorosis 187 (110 children and 77 adults) showed evidence of arthritis. The spine, especially its cervical portion, appeared to be mainly involved; elbow, hip and knee joints followed next in order.
Kidney Patients Are at Increased Risk of Fluoride Poisoning
It is well established that individuals with kidney disease are susceptible to suffering bone damage and other ill effects from low levels of fluoride exposure. Kidney patients are at elevated risk because when kidneys are damaged they are unable to efficiently excrete fluoride from the body. As a result, kidney patients
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