Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Abstract

Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen‐induced arthritis (CIA) mice synovium and bone tissues than in the noninflamed synovium and bone tissues. The CB2 selective agonist (JWH133) but not antagonist (SR144528) suppressed CIA in mice without toxic effects, as demonstrated by the decreased synovial hyperplasia, inflammatory responses, cartilage damage, and periarticular and systemic bone destruction. JWH133 treatment decreased the infiltration of pro‐inflammatory M1‐like macrophages and repolarized macrophages from the M1 to M2 phenotype. Similarly, activation of CB2 increased the expression of anti‐inflammatory cytokine interleukin (IL)‐10 and reduced the expression of pro‐inflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐1β, and IL‐6. In addition, JWH133 treatment attenuated osteoclast formation and osteoclastic bone resorption, and reduced the expression of receptor activators of the nuclear factor‐κB (NF‐κB) ligand (RANKL), matrix metallopeptidase‐9 (MMP‐9), tartrate‐resistant acid phosphatase (TRAP), cathepsin K (CTSK), and nuclear factor of activated T‐cells 1 (NFAT‐1) in CIA mice and osteoclast precursors, which were obviously blocked by pretreatment with SR144528. Mechanistically, JWH133 inhibited RANKL‐induced NF‐κB activation in the osteoclast precursors. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis. © 2018 American Society for Bone and Mineral Research.

The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases

“…Any alteration of this pathway could cause a break in the deposition–resorption equilibrium in bone tissue [62]. In RA, an increase in RANKL is in fact observed [63], and it is known that the EC system is present in RA synovial tissue and fluid [53], but not in healthy joints [64]. Also, for this pathology, the anti-inflammatory function of the EC system is crucial and moreover can be associated to the modulation of immune response.…”

Kannabinoid Tip 2 Reseptör Agonistinin Sıçanlarda Over İskemi/reperfüzyon Hasarına Karşı Koruyucu Etkisi

“…Recent studies with the activation of the CB2 receptor agonist on some diseases such as asthma, colitis, rheumatoid arthritis, rat paw infl ammation, and infl ammatory bowel disease show that it inhibits proinfl ammatory cytokine production, such as TNF-α and IL-1β, and protects it from ovarian injuries. 3,9,10,34,35 Our results show that the ovarian tissue is protected from I/R injury as it inhibits IL-1β and TNF-α levels in both ovarian tissues and serum by the activation of the CB2 receptor agonist.…”

Alterations in Anandamide Synthesis and Degradation during Osteoarthritis Progression in an Animal Model

“…JWH-015 inhibited inflammation in the rheumatoid arthritis synovial fibroblasts cell cultures and in the arthritis rat model [ 51 ]. JWH133 suppressed collagen-induced arthritis in mice, acted anti-inflammatory by repolarizing macrophages from the M1 to M2 phenotype and reduced pro-inflammatory cytokine expression [ 52 ]. CB2 agonist 4Q3C showed an anti-inflammatory effect in rheumatoid arthritis mouse model (reduced bone erosion, inhibited formation of osteoclasts and lowered the level of TNFα, IL-1β, COX-2 and inducible NO synthase) [ 53 ].…”