The genetic influence on bone susceptibility to fluoride

Mousny, Maryline; Banse, Xavier; Wise, Lisa M.; Everett, Eric T.; Hancock, R. G. V.; Vieth, Reinhold; Devogelaer, Jean‐Pierre; Grynpas, Marc D.

doi:10.1016/j.bone.2006.06.006

Cited by 56 publications

(60 citation statements)

References 37 publications

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“…Images were analyzed using image analysis software (ImageJ 1.28u; NIH), which generated data on vertebral body area (A in mm 2 ) and length (l in mm). Vertebrae were then subjected to uniaxial compression at 0.5 mm/min with a 100-N load cell on an Instron 4465 material testing system (Instron) as described (60).…”

Section: Methodsmentioning

confidence: 99%

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

Levaot¹,

Simoncic²,

Dimitriou³

et al. 2011

J. Clin. Invest.

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A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2 -/-mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cellintrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2 -/-osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2 -/-osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages. Introduction3BP2 is an adapter protein that contains an N-terminal pleckstrin homology (PH) domain, a proline-rich stretch that binds to Src homology 3 (SH3) domain-containing proteins, and a C-terminal SH2 domain that binds to phosphotyrosine residues (1). 3BP2 was initially identified as a binding protein of the tyrosine kinase Abl (2). Work from our lab and others has identified the Src family kinases (SFKs), Syk, and the Vav family of Rho guanine nucleotide exchange factors (GEFs) as 3BP2-binding partners (1), all of which are known to play important roles in osteoclast function (3-5). Cherubism is a dominantly inherited syndrome characterized by excessive maxillary and mandibular bone resorption that is associated with activated osteoclasts and inflammatory cells creating interosseous cystic lesions (6). Single missense mutations in the gene encoding the adapter protein 3BP2 result in a gain-of-function alteration in the protein and is associated with the majority of cherubism patients (7). A mouse model that harbors 2 copies of a cherubism allele develops severe osteoporosis associated with highly activated osteoclasts (8).In order to elucidate the role of the wild-type form of 3BP2 in bone homeostasis, we analyzed loss-of-function mutant mice. As distinct from the osteoporotic phenotype of mice expressing the cherubism gain-of-function form of 3BP2 associated with active osteoclasts, we uncovered a complex bone phenotype in mice lacking 3BP2 characterized by loss-of-function in both the osteoclast and osteoblast lineages resulting in net decreased bone mineral density and reduced mechanical ...

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Section: Methodsmentioning

confidence: 99%

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

Levaot¹,

Simoncic²,

Dimitriou³

et al. 2011

J. Clin. Invest.

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“…Increased fluorescence is associated with increased dental fluorosis severity. three inbred strains (A/J, SWR/J, and 129P3/J) following fluoride exposure (Mousny et al, 2006). The A/J strain demonstrated the greatest reduction in bone quality in a fluoride dose-dependent manner.…”

Section: Bone and Bone Biology Studies Involving Inbred Strains Of Micementioning

confidence: 97%

Fluoride’s Effects on the Formation of Teeth and Bones, and the Influence of Genetics

2010

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Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride's actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization.

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“…The A/J mouse strain was highly susceptible, with a rapid onset and severe development of dental fluorosis compared with the other strains tested, whereas the 129P3/J mouse strain was less affected, with minimal dental fluorosis. More recently, it has also been shown that these two strains have different bone responses to F exposure (Mousny et al, 2006).…”

Section: Influence Of Genetic Background On Fluoride Metabolism In Micementioning

confidence: 99%

Influence of Genetic Background on Fluoride Metabolism in Mice

et al. 2009

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A/J and 129P3/J mouse strains have different susceptibilities to dental fluorosis, due to their genetic backgrounds. This study tested whether these differences are due to variations in water intake and/ or F metabolism. A/J (susceptible to dental fluorosis) and 129P3/J mice (resistant) received drinking water containing 0, 10, or 50 ppm F. Weekly F intake, excretion and retention, and terminal plasma and femur F levels were determined. Dental fluorosis was evaluated clinically and by quantitative fluorescence (QF). Data were tested by twoway ANOVA. Although F intakes by the strains were similar, excretion by A/J mice was significantly higher due to greater urinary F excretion, which resulted in lower plasma and femur F levels. Compared with 129P3/J mice given 50 ppm F, significantly higher QF scores were recorded for A/J mice. In conclusion, these strains differ with respect to several features of F metabolism, and amelogenesis in the 129P3/J strain seems to be unaffected by high F exposure.KEy wORdS: dental fluorosis, fluoride metabolism, genetic susceptibility/resistance, inbred mouse strains, bone.

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The genetic influence on bone susceptibility to fluoride

Cited by 56 publications

References 37 publications

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

Fluoride’s Effects on the Formation of Teeth and Bones, and the Influence of Genetics

Influence of Genetic Background on Fluoride Metabolism in Mice

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