Targeting dysfunction glutamine-a-ketoglutarate axis attenuates osteoarthritis via maintaining metabolic homeostasis in chondrocytes

Osteoarthritis (OA) is a metabolic disorder with long-lasting low-grade inflammation, but the role for glutamine metabolism in OA pathogenesis remains unclear. Here we found that osteoarthritic cartilage had decreased levels of glutamine. Expression of glutamine transporter SLC1A5 and glutaminase (GLS1) was decreased in OA chondrocytes, with decreased production of a-ketoglutarate (aKG). Knockdown or knockout of SLC1A5 and GLS1 in cartilage leads to spontaneous OA and aggravation of cartilage destruction in mice OA models. Interestingly, we found that aKG rescued anabolism/catabolism imbalance in chondrocytes with reduced glutaminolysis and intraarticular injections of aKG effectively protected against cartilage destruction and osteophyte formation. Single-cell RNA sequencing revealed metabolic heterogeneities among subpopulations of chondrocytes and aKG supplementation rewired metabolic reprogramming including glycolysis and oxidative phosphorylation (OXPHOS) under OA circumstances. Mechanistically, aKG suppressed NF-kB activation by reducing K63-linked ubiquitination of TRAF6 to inhibit glycolysis and restore OXPHOS. Collectively, our results demonstrate that glutaminolysis dysfunction initiates and aggravates pathological changes in OA cartilage and identify aKG as a potential therapeutic metabolite for treating OA.