{"doi":"10.1093/jleuko/qiaf178","title":"TNFR2 signaling in musculoskeletal diseases: Implications for rheumatoid arthritis and osteoarthritis","abstract":"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.","journal":"Journal of Leukocyte Biology","year":2025,"id":549381,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1444082,"name":"R I Macleod","orcid":null,"position":1,"is_corresponding":false},{"id":310622,"name":"Liu C","orcid":"0000-0002-7181-8032","position":2,"is_corresponding":false},{"id":1024504,"name":"Emily Qian","orcid":"0000-0002-3304-4400","position":0,"is_corresponding":true}],"reference_count":140,"raw_metadata":null,"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41384366","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}