Synovial mesenchymal cells, matrix metalloproteinases (MMPs), and osteoclasts are the three major players directly responsible for the pathogenesis of rheumatoid joint destruction. First, synovial mesenchymal cells, internally driven by a transcription factor c-Fos/AP-1, not only directly invade cartilage and bone as a granulation tissue called "pannus" but also release inflammatory cytokine interleukin (IL)-1β. IL-1β induces MMPs and activates osteoclasts. Synovial cells can also present antigen to T cells to drive antigen-specific immune responses. Second, cartilaginous joint matrix can only be degraded after the first attack of collagen fibrils by MMPs, and importantly, most of the MMPs are under the control of c-Fos/AP-1 and IL-1β as well. Third, differentiation of osteoclast is driven internally by NFATc1, where NFATc1 is under the control of TRAF6, c-Fos/AP-1 and osteoclastogenic signaling complex. IL-1β has been shown to induce osteoclastogenesis directly and also indirectly via signaling through RANKL. Therefore, IL-1β and c-Fos/AP-1 influence each other's gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, and thus, blockade of IL-1β and/or c-Fos/AP-1 can be most promising as a therapeutic target, and in fact, a selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction.