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Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies
Sara L Dunn1, Jeremy Mark Wilkinson2, Aileen Crawford3
1Faculty of Health and Wellbeing, Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, United Kingdom.
Abstract:
Introduction: Cannabinoids have shown to reduce joint damage in animal models of arthritis and reduce matrix metalloproteinase expression in primary human osteoarthritic (OA) chondrocytes. The actions of cannabinoids are mediated by a number of receptors, including cannabinoid receptors 1 and 2 (CB1 and CB2), G-protein-coupled receptors 55 and 18 (GPR55 and GPR18), transient receptor potential vanilloid-1 (TRPV1), and peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ). However, to date very few studies have investigated the expression and localization of these receptors in human chondrocytes, and expression during degeneration, and thus their potential in clinical applications is unknown. Methods: Human articular cartilage from patients with symptomatic OA was graded histologically and the expression and localization of cannabinoid receptors within OA cartilage and underlying bone were determined immunohistochemically. Expression levels across regions of cartilage and changes with degeneration were investigated. Results: Expression of all the cannabinoid receptors investigated was observed with no change with grade of degeneration seen in the expression of CB1, CB2, GPR55, PPARα, and PPARγ. Conversely, the number of chondrocytes within the deep zone of cartilage displaying immunopositivity for GPR18 and TRPV1 was significantly decreased in degenerate cartilage. Receptor expression was higher in chondrocytes than in osteocytes in the underlying bone. Conclusions: Chondrocytes from OA joints were shown to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating that these cells could respond to cannabinoids. Cannabinoids designed to bind to receptors inhibiting the catabolic and pain pathways within the arthritic joint, while avoiding psychoactive effects, could provide potential arthritis therapies.
Insights
Cannabinoid receptors are present in osteoarthritis (OA) joint cartilage, even in degenerated tissue. This suggests cannabinoids could be developed into novel therapies for arthritis by targeting pain and degradation pathways.
Area of Science:
- Rheumatology
- Pharmacology
- Cell Biology
Background:
- Cannabinoids show potential in reducing arthritis-related joint damage and matrix metalloproteinase expression in human osteoarthritic (OA) chondrocytes.
- The therapeutic actions of cannabinoids are mediated by various receptors, including cannabinoid receptors 1 and 2 (CB1, CB2), G-protein-coupled receptors 55 and 18 (GPR55, GPR18), transient receptor potential vanilloid-1 (TRPV1), and peroxisome proliferator-activated receptors alpha and gamma (PPARα, PPARγ).
- Limited research exists on the expression and localization of these cannabinoid receptors in human chondrocytes, particularly during disease progression, hindering understanding of their clinical potential.
Purpose of the Study:
- To investigate the expression and localization of key cannabinoid receptors within human osteoarthritic (OA) cartilage and underlying bone.
- To determine how the expression of these receptors changes with the grade of cartilage degeneration in OA.
- To assess the potential of chondrocytes to respond to cannabinoid-based therapies for arthritis.
Main Methods:
- Human articular cartilage samples from patients with symptomatic OA were histologically graded.
- Immunohistochemistry was employed to determine the expression and localization of cannabinoid receptors (CB1, CB2, GPR55, GPR18, TRPV1, PPARα, PPARγ) in OA cartilage and subchondral bone.
- Expression levels were analyzed across different cartilage regions and correlated with the grade of degeneration.
Main Results:
- All investigated cannabinoid receptors were expressed in OA chondrocytes.
- Expression levels of CB1, CB2, GPR55, PPARα, and PPARγ remained unchanged with increasing degeneration grade.
- A significant decrease in chondrocytes expressing GPR18 and TRPV1 was observed in deeper zones of degenerate cartilage compared to less degenerate areas.
- Receptor expression was generally higher in chondrocytes than in osteocytes within the subchondral bone.
Conclusions:
- Human OA chondrocytes express a wide array of cannabinoid receptors, even in severely degenerated tissues, indicating their potential responsiveness to cannabinoids.
- Cannabinoids targeting specific receptors could offer novel therapeutic strategies for arthritis by modulating pain and catabolic pathways within the joint.
- Development of non-psychoactive cannabinoids targeting these receptors presents a promising avenue for future arthritis treatments.
