A study on the molecular mechanism ofcytokine-mediated inhibition of osteoblast differentiation in rheumatoid arthritis

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The cellular mechanism for cytokine-mediated inhibition of BMP-induced osteoblastic differentiation was investigated using mouse myoblast C2C12 cells. Osteoblast transformation of BMP-cultured C2C12 cells, and their Runx2/osteocalcin expression, ALP activity, and parathyroid hormone (PTH) responsiveness (cAMP production) were inhibited by TNF-α, but not by IL-1, IL-6, or IL-17. BMP-induced Smad1, 5, 8 phosphorylation in the cells was suppressed by TNF-α signaling, but inhibitory Smad6 gene activation was increased as determined by cDNA array. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated in the cells with TNF-α. BMPs had no effect on TNF type 1 and 2 receptor-expression. Notably, SAPK/JNK inhibitors restored TNF-α inhibition of osteoblast differentiation, as demonstrated by Id-1-promoter activity as well as Runx2/osteocalcin mRNA levels. These results suggest that TNF-α may have a crucial role in BMP-induced osteogenic inhibition in the diseases such as rheumatoid arthritis, through its SAPK/JNK activation and Smad6 induction.