Journal Article

Regulation of TNF-Induced Osteoclast Differentiation

Yao, Zhenqiang, Locke, Ian C., Getting, Stephen J.

2021

Overview

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Arthritis, Rheumatoid - complications / Bisphosphonates / Bone diseases / Bone loss / c-Fos protein / Cartilage / Cell Differentiation - drug effects / Dendritic cells / Fractures / Humans / Insulin / Interleukin 1 / Jagged1 protein / Kinases / Ligands / Macrophages / Mutation / NF-κB protein / nuclear factor-kappa B (NF-κB) / osteoclast / Osteoclastogenesis / Osteoclasts - cytology / Osteoclasts - drug effects / Osteoclasts - metabolism / Osteoporosis / Osteoporosis - complications / Osteoprotegerin / osteoprotegerin (OPG) / Phosphatase / receptor activator of NF-κB ligand (RANKL) / Review / Rheumatoid arthritis / Signal Transduction - drug effects / TNF receptor-associated factor 3 (TRAF3) / TRAF6 protein / TRANCE protein / Transcription factors / tumor necrosis factor alpha (TNFα) / Tumor necrosis factor receptors / Tumor Necrosis Factor-alpha - pharmacology / Tumor necrosis factor-α