TNFR2 signaling in musculoskeletal diseases: Implications for rheumatoid arthritis and osteoarthritis.

Arthritis imposes a substantial global burden and remains without curative therapy. Among the most prevalent forms, rheumatoid arthritis and osteoarthritis differ in etiology but converge on pathogenic tumor necrosis factor α (TNFα) signaling. A key regulatory node is TNFR2, which promotes immunomodulation and tissue repair in contrast to the proinflammatory signaling of TNFR1. Progranulin (PGRN), a high-affinity TNFR2 ligand, protects joints by orchestrating macrophage plasticity and chondrocyte metabolism. Central to this pathway is the adaptor protein 14-3-3ε, an essential intracellular component of the PGRN/TNFR2 complex. In macrophages, 14-3-3ε directs PI3K/Akt-mTOR signaling to restrain NF-κB and promote C/EBPβ-driven M2 polarization, while in chondrocytes it enables ERK/Elk-1 activation to sustain anabolism. Across inflammatory and degenerative models, genetic loss of PGRN, TNFR2, or 14-3-3ε abolishes protection, whereas recombinant PGRN or the engineered PGRN-derived molecule Atsttrin attenuates arthritis, preserves cartilage, and enhances bone repair. Incorporation of Atsttrin into biomaterials such as hydrogels and 3D-printed scaffolds further augments efficacy and durability in preclinical studies. This review briefly summarizes current evidence positioning the PGRN/TNFR2/14-3-3ε complex as a shared mechanism in rheumatoid arthritis and osteoarthritis pathogenesis and repair, and highlights translational opportunities-from TNFR2 agonism to Atsttrin-based therapeutics-for disease modification in arthritis.