The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorption

Abstract

The contribution of osteoclasts to the process of bone loss in inflammatory arthritis has recently been demonstrated. Studies in osteoclast biology have led to the identification of factors responsible for the differentiation and activation of osteoclasts, the most important of which is the receptor activator of NF-kappa B ligand/osteoclast differentiation factor (RANKL/ODF), a tumor necrosis factor (TNF)-like protein. The RANKL/ODF receptor, receptor activator of NF-kappa B (RANK), is a TNF-receptor family member present on both osteoclast precursors and mature osteoclasts. Like other TNF-family receptors and the IL-1 receptor, RANK mediates its signal transduction via TNF receptor-associated factor (TRAF) proteins, suggesting that the signaling pathways activated by RANK and other inflammatory cytokines involved in osteoclast differentiation and activation are interconnected.

Figure 1

Simplified schematic view of the interactions between membrane-bound RANKL on osteoblast/bone stromal cells and its receptor RANK on osteoclast precursor cells. This interaction leads to the differentiation of osteoclast precursor cells and the activation of osteoclasts to resorb bone. OPG can inhibit this interaction by binding to membrane-bound RANKL and blocking the RANKL-RANK interaction. D₃, vitamin D₃; M-CSF, macrophage-colony stimulating factor; OC, osteoclast.

Figure 2

Interrelationships among receptors that signal via TRAFs. Double-headed, dashed arrows indicate known direct protein-protein interactions; solid arrows represent enzymatic and functional pathways. Emphasis is placed on distinctions between osteoclastogenesis and osteoclast activation. Abbreviations and terms are defined in the text.