ELUCIDATING DISEASE-MODIFYING MECHANISMS OF DELTA-9-TETRAHYDROCANNABINOL IN PRE-CLINICAL OSTEOARTHRITIS

Purpose: Osteoarthritis (OA) affects all joint tissues, including cartilage and synovium. Significant pain, disability, and a decreased quality of life result from OA joint degeneration. Current treatments available provide only temporary symptomatic relief, cause negative side-effects, or are ineffective, supporting the need for efficacious symptom- and disease-modifying therapies. Patients with OA use cannabinoid products to alleviate chronic pain symptoms. However, minimal research exists on the impact of cannabinoids on OA pain and disease pathogenesis; thus, there is insufficient evidence-based knowledge about the appropriate use of cannabis products as OA therapy. Our initial pre-clinical results suggest that administration of 10 mg/kg Δ⁹-tetrahydrocannabinol (THC) by oral gavage, but not by intraarticular (IA) injection, significantly reduces pain and joint degeneration in the destabilization of the medial meniscus (DMM) mouse model of OA. Regardless of the route of administration, THC likely reaches the joint and signals through numerous receptors expressed on joint cells, including the CB₁ and CB₂ cannabinoid receptors. Signaling downstream of CB₁ and CB₂ inhibits the adenylate cyclase enzyme, resulting in reductions of intracellular cAMP levels. However, the effects of THC on fibroblast-like synoviocytes (FLS) and chondrocytes in the OA joint, and its mechanisms of disease modification, remain unknown. Thus, we sought to determine mechanisms by which THC modifies OA disease pathogenesis by investigating cell survival, inflammation, and homeostasis in joint cells and tissues.