Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid
Open accessAbstract
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 PPARγ directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast‐like synovial cells (FLS), and examined the role of PPARγ in the mechanism of action of AjA. FLS, treated or not with a PPARγ antagonist, were treated with AjA then stimulated with TNFα or IL‐1α. Release of MMPs‐1, 3, and 9 was measured by ELISA. The influence of AjA on MMP‐3 release from stimulated PPARγ positive (PPAR+/−) and PPARγ null (PPAR−/−) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARγ activation was blocked. Secretion of MMP‐3 was also suppressed by AjA in both TNFα‐ and IL‐1α‐stimulated PPARγ+/−and PPARγ−/−MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARγ independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be 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. J. Cell. Biochem. 100: 184–190, 2007. © 2006 Wiley‐Liss, Inc.
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In fibroblast-like synoviocytes derived from patients with rheumatoid arthritis and osteoarthritis, synthetic cannabinoid receptor agonists (CP55,940, WIN55,212, or Ajulemic acid) or AEA attenuate TNF-α stimulated production of the proinflammatory cytokines IL-6 and IL-8, and matrix degrading enzymes matrix metalloproteinases-1, -3, and -9.
“In FLSs derived from patients with rheumatoid arthritis and osteoarthritis, synthetic cannabinoid receptor agonists (CP55,940, WIN55,212, or Ajulemic acid) or AEA (Lowin et al, 2015) attenuate TNF-α stimulated production of the proinflammatory cytokines IL-6 and IL-8, and matrix degrading enzymes matrix metalloproteinases-1, -3, and -9 (Johnson et al, 2007;Lowin et al, 2015Lowin et al, , 2016;;Sel”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Johnson et al, 2007
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- Authors
- Johnson, D. R., Stebulis, J. A., Rossetti, R. G., Burstein, S. H., & Zurier, R. B.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Zurier, Robert B.
- Venue
- Journal of Cellular Biochemistry
- Publisher
- Wiley
- Published
- 2006-08-22
- Volume
- 100
- Issue
- 1
- Pages
- 184-190
- ISSN
- 0730-2312 (ISSN-L)
- 1097-4644
- OpenAlex
- W1981523545
- Cited by
- 41
- References
- 29
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 3
- FWCI
- 2.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R01 DA 13691, R01DA013691)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007572, T32 AR07572)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- ajulemic acid, matrix metalloproteinases, PPARγ-independent mechanism, synovial fibroblasts, adjuvant-induced arthritis, rheumatoid arthritis, osteoarthritis, MMP-3, MMP-1, MMP-9, TNF-α, IL-1α, cartilage degeneration
- MeSH terms
- Animals, Arthritis, Experimental, Cartilage, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Fibroblasts, Humans, Synovial Fluid, Dronabinol, Tumor Necrosis Factor-alpha, Mice, Knockout, Antirheumatic Agents, Matrix Metalloproteinases, PPAR gamma, Mice, Rats, Interleukin-1alpha, Matrix Metalloproteinase Inhibitors
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