Role of the Interaction of Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors 1 and 2 in Bone-Related Cells

Abstract

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine expressed by macrophages, monocytes, and T cells, and its expression is triggered by the immune system in response to pathogens and their products, such as endotoxins. TNF-α plays an important role in host defense by inducing inflammatory reactions such as phagocytes and cytocidal systems activation. TNF-α also plays an important role in bone metabolism and is associated with inflammatory bone diseases. TNF-α binds to two cell surface receptors, the 55kDa TNF receptor-1 (TNFR1) and the 75kDa TNF receptor-2 (TNFR2). Bone is in a constant state of turnover; it is continuously degraded and built via the process of bone remodeling, which results from the regulated balance between bone-resorbing osteoclasts, bone-forming osteoblasts, and the mechanosensory cell type osteocytes. Precise interactions between these cells maintain skeletal homeostasis. Studies have shown that TNF-α affects bone-related cells via TNFRs. Signaling through either receptor results in different outcomes in different cell types as well as in the same cell type. This review summarizes and discusses current research on the TNF-α and TNFR interaction and its role in bone-related cells.

Keywords: TNF receptor-1; TNF receptor-2; TNF-α; osteoblast; osteoclast; osteocyte.

Figure 1

Schematic of the interaction of tumor necrosis factor-α (TNF-α) and tumor necrosis factor receptors 1 and 2 (TNFR1 and TNFR2) in bone-related cells, osteoclasts, osteoblasts, and osteocytes. TNF-α induces osteoclast formation and activates transcription factor AP-1 through phosphorylation of MAPKs (ERK, p38, and JNK) and induces activation of transcription factor NF-κB through phosphorylation of IκB in osteoclast precursors via TNFR1. On the other hand, TNF-α inhibits osteoclast differentiation via TNFR2. TNF-α induced an anti-apoptotic effect by mTOR signaling by activated Src and Akt. mTOR regulates protein translation through S6K, 4E-BP1, S6, and elF4E, and inhibits osteoclast apoptosis. TNF-α induces RANKL expression by MAPKs and NF-κB activation in osteoblasts but inhibits osteoclast differentiation via TNFR1. TNF-α induces RANKL expression by activation of MAPKs and NF-κB in osteocytes.