Bone Response to Fluoride Exposure Is Influenced by Genetics

Abstract

Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined. A label-free proteomics approach was employed to identify and evaluate changes in bone protein expression in two mouse strains having different susceptibilities to develop dental fluorosis and to alter bone quality. In vivo bone formation and histomorphometry after F intake were also evaluated and related to the proteome. Resistant 129P3/J and susceptible A/J mice were assigned to three groups given low-F food and water containing 0, 10 or 50 ppmF for 8 weeks. Plasma was evaluated for alkaline phosphatase activity. Femurs, tibiae and lumbar vertebrae were evaluated using micro-CT analysis and mineral apposition rate (MAR) was measured in cortical bone. For quantitative proteomic analysis, bone proteins were extracted and analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), followed by label-free semi-quantitative differential expression analysis. Alterations in several bone proteins were found among the F treatment groups within each mouse strain and between the strains for each F treatment group (ratio ≥1.5 or ≤0.5; p<0.05). Although F treatment had no significant effects on BMD or bone histomorphometry in either strain, MAR was higher in the 50 ppmF 129P3/J mice than in the 50 ppmF A/J mice treated with 50 ppmF showing that F increased bone formation in a strain-specific manner. Also, F exposure was associated with dose-specific and strain-specific alterations in expression of proteins involved in osteogenesis and osteoclastogenesis. In conclusion, our findings confirm a genetic influence in bone response to F exposure and point to several proteins that may act as targets for the differential F responses in this tissue.

The incorporation of fluoride and strontium in hydroxyapatite affects the composition, structure, and mechanical properties of human cortical bone

“…An explanation for the differences in fluoride concentration within the bone matrix might be a different genetic susceptibility to fluoride. Studies in mice have already shown that the effect of fluoride on bone differs between different mice strains . The distribution pattern of fluoride is shown in Figure (F) in bone from an individual after a treatment period of 60 months.…”

“…Studies in mice have already shown that the effect of fluoride on bone differs between different mice strains. [32][33][34] The distribution pattern of fluoride is shown in Figure 2(F) in bone from an individual after a treatment period of 60 months. Due to the limited sensitivity of the PIXE method to fluoride the mapping of fluoride was done by the detection of a-particles from the 19 F(p, a) 16 O nuclear reaction.…”

Association between vitamin D receptor gene FokI polymorphism and skeletal fluorosis of the brick-tea type fluorosis: a cross sectional, case control study

“…Not everyone living in areas with naturally high fluoride levels in water suffers from fluorosis 526 Three inbred strains of mice (A/J, SWR/J and 129P3/J) that showed different susceptibilities to dental fluorosis displayed variations in bone response to fluoride exposure 27–29. Hence genetics may influence the bone response of individuals to fluoride exposure.…”

Progressive Research in the Molecular Mechanisms of Chronic Fluorosis

“…Excessive intake of fluoride affects the bone matrix proteins, that is, collagen and noncollagenous proteins, which may be another possible mechanism of skeletal fluorosis [42,54]. For example, it has been shown that fluoride could inhibit the synthesis of type I collagen and decrease the degree of collagen cross-linking [54][55][56][57][58][59] or affect other collagen proteins [60][61][62], and affect the synthesis of proteoglycan [63], and expression of matrix metalloproteinases (MMPs) [54, 64,65]. Taken together, these studies suggested that exposure to fluoride alters growth, ECM formation, bone mineralization, and skeletal development and induced bone formation and bone resorption, thus leading to the development of fluorosis.…”