Opposing Synovial Cannabinoid Receptor Type 2 and Transient Receptor Potential Vanilloid 1 Expression in Painful Osteoarthritis

Knee osteoarthritis (kOA) poses a major health challenge worldwide, but current non-surgical treatments have limited long-term success and do not address the underlying disease process. This study explores the complex relationship between the endocannabinoid system (ECS) and the endovanilloid system (EVS) in the synovial membrane of patients with kOA undergoing total knee replacement, focusing on how these systems relate to patient-reported pain and histological synovitis. Synovial tissues and fluid from patients grouped into high and low pain categories based on the Knee Injury and Osteoarthritis Outcome Score (KOOS) were examined for cannabinoid receptor type 2 (CB2R), transient receptor potential vanilloid 1 (TRPV1), protein gene product 9.5 (PGP9.5), calcitonin gene-related peptide (CGRP), and endocannabinoids (2-arachidonoylglycerol (2-AG) and anandamide (AEA)). Results show that higher reported pain and more severe synovitis are linked to significantly lower levels of synovial CB2R and higher TRPV1 expression. Higher levels of synovial fluid (SF) 2-AG were also found in high-pain groups, along with a trend toward increased CGRP levels. The distribution of PGP9.5 did not differ significantly between groups. These findings collectively suggest a dysregulated TRPV1/CB2R axis in painful kOA synovitis. This research offers key descriptive data and important initial insights into the molecular landscape of painful kOA, indicating potential for targeted CB2R-specific treatments to help manage pain and inflammation.