HU308 Mitigates Osteoarthritis by Stimulating Sox9‐Related Networks of Carbohydrate Metabolism

Osteoarthritis (OA) is characterized by progressive, irreversible erosion of articular cartilage accompanied with severe pain and immobility. This study aimed to assess the effect and mechanism of action of HU308- a selective cannabinoid receptor type 2 (CB2) agonist, in potentially preventing OA-related joint damage. To test this assumption, Cn2r null mice and Wild type (WT) mice were aged to reach 20 months, and analyzed for joint structural features. OA was induced in WT mice via post-traumatic procedure or ageing, followed by HU308 local (intra-articular) or systemic (intraperitoneal) administration, respectively. Additional analysis of time and dose courses for HU308 were carried out in human primary chondrocytes, analyzed by RNA-sequencing, RT-PCR, ChIP and immunoblotting. Our results show that Cnr2 null mice exhibited enhanced age-related OA severity and synovitis compared to age-matched WT mice. Systemic administration of HU308 to 16-month mice improved pain sensitivity and maintained joint integrity, which was consistent with the intra-articular administration of HU308 in post-traumatic OA mice. When assessing human chondrocytes treated with HU308, we uncovered a dose- and time related increase in ACAN and COL2A1 expression, which was preceded by increased SOX9 expression due to pCREB transcriptional activation of the SOX9 gene. Finally, transcriptomic analysis of patient-derived human chondrocytes, identified patient subpopulations exhibiting HU308 responsive trends as judged by enhanced SOX9 expression, accompanied by enriched gene networks related to carbohydrate metabolism. Collectively, the results show that HU308 reduced trauma and age-induced OA, via CB2-pCREB dependent activation of SOX9, contributing to augmented genes networks related to carbohydrate metabolism. This article is protected by copyright. All rights reserved.