This review emphasizes our first discovery on the contribution of over-activation of c-fos gene to the pathogenesis of rheumatoid joint destruction. In particular, c-Fos signalling was required for increased activity of synovial mesenchymal cells which finally leads to rheumatoid joint destruction and peri-articular osteoporosis. Over-activation of c-fos via Wee1 kinase is responsible for tumor-like synovial over-growth. Our team designed anti-c-Fos drugs that specifically inhibit action of c-Fos at the AP-1 consensus sequence by using a computer-assisted drug design, which was the front-runner work executed in Japan.