Figure 3

View into an erosion: mechanisms involved in osteoclastogenesis and arthritic bone erosion. The resorption front of local bone erosion in rheumatoid arthritis (RA) is illustrated. A resorption lacuna is filled with an osteoclast and surrounded by synovial inflammatory tissue (pannus) with fibroblast-like synoviocytes and T cells. Both of these cell types influence osteoclast maturation and activation, whereas cells of the macrophage lineage, which are not separately depicted, constitute the pool of osteoclast precursor cells. Potential therapeutic targets, which also represent essential mechanisms of osteoclast development and function, are indicated by black squares. Target molecules are grouped according to their functional role in the osteoclast (from the top): molecules, which influence the stromal cells to express pro-osteoclastogenic molecules (such as tumor necrosis factor [TNF], IL-1, IL-6, IL-11, IL-17 or prostaglandin E₂ [PGE₂]); receptor-ligand interactions, which are essential for osteoclast development and function (receptor-activator of nuclear factor kappa B ligand [RANKL]/receptor-activator of nuclear factor kappa B [RANK], macrophage-colony-stimulating factor (M-CSF)/c-fms, RGD-containing matrix molecules/avβ3 integrin); signaling intermediates downstream of the receptor level (src, TRAF-6, PI3-K); phosphokinases in the cytoplasm (akt, JNK, p38, ERK); transcription factors (c-fos, c-jun, nuclear factor [NF]-κB); and effector molecules essential for osteoclast function (cathepsin K, matrix metalloproteinase [MMP]-9, vATPase). The bar between the osteoclast and the bone indicates one of the complex methods of the function of bisphosphonates (inhibition of attachment of osteoclasts on bone), whereas other methods such as inhibition of the mevalonate pathway are not depicted.