Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid

Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPAR gamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPAR gamma in the mechanism of action of AjA. FLS, treated or not with a PPAR gamma antagonist, were treated with AjA then stimulated with TNF alpha or IL-1 alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPAR gamma positive (PPAR(+/-)) and PPAR gamma null (PPAR(-/-)) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPAR gamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNF alpha- and IL-1 alpha-stimulated PPAR gamma(+/-) and PPAR gamma(-/-) MEF. Suppression of MMP secretion from FLS by AjA appears to be PPAR gamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may he explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.