Bad to Bone: Homocysteine

Abstract

Children born with severe homocystinuria i.e. mutation of the cystathionine‐â‐synthase (CBS) gene resulting in an elevation in plasma homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), develop skeletal mal‐formation with weaker bones.. Therefore present study examined the mechanism of changes in bone structure/function during HHcy. There were four groups of mice: WT, CBS+/−, WT+ Folic Acid (FA), CBS+/− + FA (0.03gm/L in drinking water for 6 weeks). The tibial bone blood flow was measured by laser Doppler. The tibial bone density was assessed by dual energy X‐ray absorptiometry. The tibia bone homogenates were analyzed for total Hcy, SAHH, CBS and MTHFR levels. MMP‐9 activity was measured by zymography and RT‐PCR. The levels of TIMPs were measured by Western blots, reverse zymography, RT‐PCR and immunehistochemistry. The levels of osteoblast/osteoclast/osteocyte were detected by immunohistochemistry and TRAP staining. The results suggested that there was decrease in bone blood flow in CBS+/− mice. The bone density was also reduced in CBS+/− mice. There was an increase in SAHH, MMP‐9 protein as well as MMP‐9 activity in CBS+/− mice and decrease in MTHFR, TIMP‐1,‐2 protein as well as mRNA levels, in part by increasing total Hcy level in CBS+/− mice. Interestingly, these effects were ameliorated by FA and suggested therapeutic role of FA in genetically HHcy induced bone disease.