Figure 4.

Mechanisms influencing TRAF3 functions and degradation in osteoclast and osteoblast precursors. Multiple pathologic processes and aging can increase production of cytokines, such as TNF, IL-1 and IL-6 (1), to increase production of RANKL by accessory cells, including mesenchymal progenitor (MPCs), osteoblastic (OB), and T and B lymphocytes (2). RANKL binding to RANK in osteoclast precursors results in TRAF3 ubiquitination and lysosomal degradation (3), thus allowing NF-κB-inducing kinase (NIK) to mediate proteasomal processing of p100 to 52 (4) and formation of p52/RelB heterodimers to promote osteoclast formation and bone resorption (5). Inhibitors of lysosomal degradation, such as chloroquine, can prevent degradation of TRAF3, which will promote NIK degradation and inhibit osteoclast formation (7). TRAF3 expression in MPCs also promotes their differentiation into OBs and limits their production of RANKL to maintain bone formation and restrict bone resorption (8).