Review: Novel Insights Into Tumor Necrosis Factor Receptor, Death Receptor 3, and Progranulin Pathways in Arthritis and Bone Remodeling.

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Approximately 30 members of the tumor necrosis factor receptor superfamily (TNFRSF) have been identified. They are transmembrane proteins with cysteine‐rich motifs in their extracellular domains that bind to their cognate ligands 1. They are categorized into 3 groups: death domain–containing receptors, decoy receptors, and TNFR‐associated factor–binding receptors. Only 8 TNFRSF members contain a death domain (TNFR type I [TNFRI], death receptor 3 [DR‐3], DR‐4, DR‐5, DR‐6, Fas, nerve growth factor receptor, and ectodysplasin A receptor [EDAR]), of which TNFRI and DR‐3 constitute the principal focus of this article. Interactions between TNF superfamily (TNFSF) ligands and TNFRSF receptors help maintain tissue homeostasis by controlling survival, proliferation, differentiation, and effector function of immune cells. We limit our review to recent advances and novel insights into the roles of TNFRI and DR‐3 in bone and joint biology. Bone cells (osteoblasts, osteoclasts, and osteocytes), fibroblast‐like synoviocytes, chondrocytes, and immune cells that infiltrate the arthritic joint will at different times express a wide range of TNFRSF members and TNFSF ligands. An overview of the current status of our knowledge in this regard is provided in Table 1. The impact of TNFRI activation on bone and inflammatory joint diseases has been researched in great depth 2, 3, but little or no data in the field have been reported on other more recently discovered TNFRSF members such as TROY (TNFRSF expressed on the mouse embryo; TNFRSF19), EDAR, and XEDAR (X‐linked ectodysplasin receptor; TNFRSF27). The unexpected interaction between progranulin (PGRN) and both TNFRI and TNFRII is particularly interesting in the context of arthritis‐associated bone pathology. PGRN levels are elevated in the synovial fluid of patients with rheumatoid arthritis (RA), osteoarthritis (OA), and other arthropathies 4, 5, 6, and PGRN has been shown to inhibit TNF‐induced osteoclastogenesis and promote osteoblast differentiation in mice 7. However, PGRN has a higher binding affinity for TNFRII (antiinflammatory with osteoprotective function) than for TNFRI (predominantly proinflammatory with degenerative function), which suggests conflicting actions. The potential overall impact of these divergent PGRN signaling pathways on the architecture of the arthritic joint has been evaluated 8. Table 1 Cellular expression of death domain–containing TNFRSF members and their association with arthritis*