{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:36:22Z","timestamp":1790109382128,"version":"4.0.1"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Osteoarthritis (OA) is traditionally framed as a degenerative cartilage disease caused by age-related mechanical wear. However, this paradigm does not adequately account for the synovitis, metabolic disturbance, and pain that commonly precede overt structural loss. In this Hypothesis and Theory article, we propose a testable systems model in which OA reflects a failure of interdependent synovial regulatory networks rather than a purely structural endpoint. These networks include: (1) energy-redox imbalance driven by declining NAD+\u202favailability and mitochondrial inefficiency, which may prime synovial inflammation; (2) dysregulated MRP4- and MCT4-dependent efflux, leading to extracellular accumulation of prostaglandins and lactate that may promote nociception and stromal activation; (3) reduced protein phosphatase 2A (PP2A)-mediated signaling restraint, which may permit persistence of NF-\u03baB and MAPK phosphorylation; and (4) impaired lipid mediator class switching, which may limit biosynthesis of specialized pro-resolving mediators such as Maresin-2 and Resolvin D1. We further propose that microtubule organization may function as a mechanometabolic interface linking redox decline, lactate signaling, transporter localization, and impaired mechanosensing. Because current anti-inflammatory therapies largely suppress inflammatory output rather than restore regulatory control, they may provide symptomatic relief without durable disease modification. We therefore outline a regulatory-restoration framework focused on NAD+\u202f-redox alignment, mediator transport, phosphatase tone, and resolution-pathway recovery, while explicitly defining the limitations and falsifiable predictions of the model.<\/jats:p>","DOI":"10.3389\/fmed.2026.1843245","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:44:00Z","timestamp":1779943440000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond cartilage degeneration: osteoarthritis as a systems failure of inflammation regulation"],"prefix":"10.3389","volume":"13","author":[{"given":"David","family":"Bar-Or","sequence":"first","affiliation":[{"name":"Department of Trauma Research, Swedish Medical Center","place":["Englewood, CO, United 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