The Role of TNFα in Down‐Regulation of Osteoblast Phex Gene Expression in Experimental Colitis

Reduced bone mass is a common complication of IBD; however the mechanisms contributing to osteopenia are not completely understood. TNFα is upregulated in patients with IBD and has negative effects on osteoblasts. Phex gene is expressed primarily in osteoblasts and its disruption results in defective bone mineralization. The aim of this study was to evaluate whether TNFα regulates Phex gene expression thus contributing to the abnormal bone metabolism observed in IBD. Phex mRNA expression was evaluated in calvaria of 6 week old mice administered intrarectally with TNBS or systemically with TNFα and in TNFα treated UMR‐106 osteoblast cells. Phex promoter activity was assayed in transiently transfected UMR‐106 cells treated with TNFα. Phex mRNA expression decreased 40–50% in TNBS colitis and in TNFα‐injected mice. Local attenuation of colitis and TNFα expression by dietary curcumin counteracted the detrimental effect of TNBS on Phex expression. TNFα treated UMR‐106 cells showed a concentration‐dependent and transcriptionally‐mediated decrease in Phex mRNA and gene promoter activity, with the −133 to −74 bp region of the Phex promoter likely involved in the mechanism of TNFα action. Matching decreased Phex protein levels, TNFα drastically reduced mineralization in UMR‐106 cells. In conclusion, acute colitis and TNFα decreases Phex mRNA and protein expression via a transcriptional mechanism. Thus, TNFα‐mediated reduction of Phex protein may in part be responsible for inhibition of osteoblast mineralization, thus contributing to the abnormal bone metabolism associated with IBD. Supported by R01‐DK33209.