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Among the most prevalent forms, rheumatoid arthritis and osteoarthritis differ in etiology but converge on pathogenic tumor necrosis factor \u03b1 (TNF\u03b1) 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 14-3-3\u03b5, an essential intracellular component of the PGRN\/TNFR2 complex. In macrophages, 14-3-3\u03b5 directs PI3K\/Akt-mTOR signaling to restrain NF-\u03baB and promote C\/EBP\u03b2-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 14-3-3\u03b5 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\/14-3-3\u03b5 complex as a shared mechanism in rheumatoid arthritis and osteoarthritis pathogenesis and repair, and highlights translational opportunities\u2014from TNFR2 agonism to Atsttrin-based therapeutics\u2014for disease modification in arthritis.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf178","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T13:11:54Z","timestamp":1765458714000},"source":"Crossref","is-referenced-by-count":1,"title":["TNFR2 signaling in musculoskeletal diseases: Implications for rheumatoid arthritis and osteoarthritis"],"prefix":"10.1093","volume":"118","author":[{"given":"Emily","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Orthopaedics and Rehabilitation, Yale University School of Medicine , 789 Howard Avenue, New Haven, CT 06519 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan S","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Rehabilitation, Yale University School of Medicine , 789 Howard Avenue, New Haven, CT 06519 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7181-8032","authenticated-orcid":false,"given":"Chuan-Ju","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Rehabilitation, Yale University School of Medicine , 789 Howard Avenue, New Haven, CT 06519 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"2026012811052470900_qiaf178-B1","doi-asserted-by":"publisher","first-page":"e508","DOI":"10.1016\/s2665-9913(23)00163-7","article-title":"Global, regional, and national burden of 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