Assessment of the impact of hyperhomocysteinemia on bone using the methylenetetrahydrofolate reductase-deficient mouse model

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in homocysteine metabolism. A common polymorphism in the MTHFR gene (677C→T) can result in the condition hyperhomocysteinemia when concurrent with low dietary folate intake. In several clinical studies, this polymorphism has been associated with low bone mineral density and increased fracture risk.; The MTHFR knockout mouse, a model for human hyperhomocysteinemia, was used to further investigate the bone phenotype associated with this condition by comparing heterozygous mutants to wild-type animals. Effects of a low folate diet were also assessed.; Bone strength was not decreased, and osteoclast numbers were not increased in heterozygotes or due to low folate. Expression levels of several genes involved in protection against oxidative stress were altered in heterozygotes as compared to wild-types. Bone mineral density was decreased and bone architecture changed as a result of low folate intake, especially in heterozygotes. These findings shed light on possible mechanisms of homocysteine toxicity in bone.