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Bone response to fluoride exposure is influenced by genetics.

Kobayashi CA, Leite AL, Peres-Buzalaf C, Carvalho JG, Whitford GM, Everett ET, Siqueira WL, Buzalaf MA - PLoS ONE (2014)

Bottom Line: Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.

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.

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Schemes of the protein-based mechanisms triggered by F in osteoblasts and osteoclasts.Identified proteins with greater abundance in 129P3/J in comparison to A/J related to bone metabolism are shown in red. (A) Exportin enhances transport of cfab/Runx-2 to the nucleus activating transcription of collagen type I genes. Cadherins promote intercellular adhesion enhancing osteoblast differentiation. Nox-mediated ROS production enhances RANK ligand (RANKL) that interacts to its receptor (RANK) to induce osteoclast differentiation. (B) The treatment of 129P3/J with high F promotes enhancement of Nox, CDH, cadherin, catetin and SHIP while (C) in A/J, F at high dose promotes enhancement of SHIP and reduction of exportin.
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pone-0114343-g006: Schemes of the protein-based mechanisms triggered by F in osteoblasts and osteoclasts.Identified proteins with greater abundance in 129P3/J in comparison to A/J related to bone metabolism are shown in red. (A) Exportin enhances transport of cfab/Runx-2 to the nucleus activating transcription of collagen type I genes. Cadherins promote intercellular adhesion enhancing osteoblast differentiation. Nox-mediated ROS production enhances RANK ligand (RANKL) that interacts to its receptor (RANK) to induce osteoclast differentiation. (B) The treatment of 129P3/J with high F promotes enhancement of Nox, CDH, cadherin, catetin and SHIP while (C) in A/J, F at high dose promotes enhancement of SHIP and reduction of exportin.

Mentions: Taken together, 129P3/J and A/J mice have intrinsic molecular differences related to bone metabolism (Fig. 6A). They also differ in response to F. 129P3/J mice responded similarly at high and low F doses, increasing the level of proteins involved in bone formation, as well as in bone resorption (Fig. 6B), a similar profile observed for low F-treated A/J mice. Instead, high F treatment diminishes level of proteins related to bone remodeling (Fig. 6C). These findings are consistent with known differences in susceptibility to F effect on mineralized tissues between these strains. The A/J mouse strain is more sensitive to develop dental fluorosis and to alterations in the quality of bone, while 129P3/J is less affected. Proteomic data revealed that bones of A/J mice were highly responsive to F which altered the abundance of 36 proteins even at the low dose level. At the higher F exposure level, A/J mice had 17 proteins with differences in expression compared to the control (untreated) mice. On the other hand, the treatment of 129P3/J mice with low and high doses of F altered 29 and 127 proteins, respectively. The greater responsiveness to high dose of F suggests that, possibly due to its resistance, 129P3/J requires a higher dose to trigger cytotoxic, detox and anabolic responses. Thus, at the higher dose F can stimulate bone formation in 129P3/J mice and either not change or decrease it in A/J mice.


Bone response to fluoride exposure is influenced by genetics.

Kobayashi CA, Leite AL, Peres-Buzalaf C, Carvalho JG, Whitford GM, Everett ET, Siqueira WL, Buzalaf MA - PLoS ONE (2014)

Schemes of the protein-based mechanisms triggered by F in osteoblasts and osteoclasts.Identified proteins with greater abundance in 129P3/J in comparison to A/J related to bone metabolism are shown in red. (A) Exportin enhances transport of cfab/Runx-2 to the nucleus activating transcription of collagen type I genes. Cadherins promote intercellular adhesion enhancing osteoblast differentiation. Nox-mediated ROS production enhances RANK ligand (RANKL) that interacts to its receptor (RANK) to induce osteoclast differentiation. (B) The treatment of 129P3/J with high F promotes enhancement of Nox, CDH, cadherin, catetin and SHIP while (C) in A/J, F at high dose promotes enhancement of SHIP and reduction of exportin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263599&req=5

pone-0114343-g006: Schemes of the protein-based mechanisms triggered by F in osteoblasts and osteoclasts.Identified proteins with greater abundance in 129P3/J in comparison to A/J related to bone metabolism are shown in red. (A) Exportin enhances transport of cfab/Runx-2 to the nucleus activating transcription of collagen type I genes. Cadherins promote intercellular adhesion enhancing osteoblast differentiation. Nox-mediated ROS production enhances RANK ligand (RANKL) that interacts to its receptor (RANK) to induce osteoclast differentiation. (B) The treatment of 129P3/J with high F promotes enhancement of Nox, CDH, cadherin, catetin and SHIP while (C) in A/J, F at high dose promotes enhancement of SHIP and reduction of exportin.
Mentions: Taken together, 129P3/J and A/J mice have intrinsic molecular differences related to bone metabolism (Fig. 6A). They also differ in response to F. 129P3/J mice responded similarly at high and low F doses, increasing the level of proteins involved in bone formation, as well as in bone resorption (Fig. 6B), a similar profile observed for low F-treated A/J mice. Instead, high F treatment diminishes level of proteins related to bone remodeling (Fig. 6C). These findings are consistent with known differences in susceptibility to F effect on mineralized tissues between these strains. The A/J mouse strain is more sensitive to develop dental fluorosis and to alterations in the quality of bone, while 129P3/J is less affected. Proteomic data revealed that bones of A/J mice were highly responsive to F which altered the abundance of 36 proteins even at the low dose level. At the higher F exposure level, A/J mice had 17 proteins with differences in expression compared to the control (untreated) mice. On the other hand, the treatment of 129P3/J mice with low and high doses of F altered 29 and 127 proteins, respectively. The greater responsiveness to high dose of F suggests that, possibly due to its resistance, 129P3/J requires a higher dose to trigger cytotoxic, detox and anabolic responses. Thus, at the higher dose F can stimulate bone formation in 129P3/J mice and either not change or decrease it in A/J mice.

Bottom Line: Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.

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.

Show MeSH
Related in: MedlinePlus