CircRNA HIPK2-mediated metabolic reprogramming restores mitochondrial homeostasis in chondrocytes through the miR-206/Sirt3 signaling axis attenuating osteoarthritis-induced nociception.

Abstract

Osteoarthritis (OA) is a degenerative joint disorder marked by chondrocyte metabolic dysfunction and mitochondrial impairment. This study elucidates the role of circHIPK2, a circular RNA downregulated in OA chondrocytes, in regulating glucose metabolism and mitochondrial homeostasis through the miR-206-SIRT3 axis. Clinical samples revealed significant circHIPK2 reduction and miR-206 upregulation in OA chondrocytes, correlating inversely with SIRT3 expression. In vitro LPS-induced injury models demonstrated that circHIPK2 overexpression mitigated chondrocyte apoptosis and metabolic stress, while miR-206 inhibition reversed LPS-driven glycolytic activation and mitochondrial dysfunction. Mechanistically, circHIPK2 directly bound miR-206 via Ago2-dependent interactions, as confirmed by RNA pull-down and luciferase assays, thereby alleviating miR-206-mediated suppression of SIRT3, a key mitochondrial deacetylase. Rescue experiments in chondrocytes showed that SIRT3 restoration rescued miR-206-induced metabolic defects, including impaired oxidative phosphorylation and ATP depletion. In vivo, intra-articular delivery of circHIPK2 in a monosodium iodoacetate (MIA)-induced OA rat model attenuated mechanical allodynia, cartilage degradation, and aberrant miR-206/SIRT3 expression, while improving weight-bearing symmetry; furthermore, similar therapeutic benefits-including pain relief, functional recovery, and cartilage protection-were confirmed in a chronic, post-traumatic destabilization of the medial meniscus (DMM) model, with efficacy demonstrated against appropriate AAV control groups. These findings identify the circHIPK2-miR-206-SIRT3 axis as a critical regulator of chondrocyte bioenergetics and OA progression, offering novel therapeutic targets for modulating non-coding RNA networks in joint degeneration.