GLI1 facilitates collagen-induced arthritis in mice by collaborative regulation of DNA methyltransferases.

Rheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Many types of cells are involved in the progression of RA joint inflammation, among which the overactivation of M1 macrophages and osteoclasts has been thought to be an essential cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1 expression in the synovial tissue of RA patients was positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interactions. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitors in the clinical treatment of RA.

Prevention and treatment of inflammatory arthritis with traditional Chinese medicine: Underlying mechanisms based on cell and molecular targets.

Inflammatory arthritis, primarily including rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, is a group of chronic inflammatory diseases, whose general feature is joint dysfunction with chronic pain and eventually causes disability in older people. To date, both Western medicine and traditional Chinese medicine (TCM) have developed a variety of therapeutic methods for inflammatory arthritis and achieved excellent results. But there is still a long way to totally cure these diseases. TCM has been used to treat various joint diseases for thousands of years in Asia. In this review, we summarize clinical efficacies of TCM in inflammatory arthritis treatment after reviewing the results demonstrated in meta-analyses, systematic reviews, and clinical trials. We pioneered taking inflammatory arthritis-related cell targets of TCM as the entry point and further elaborated the molecular targets inside the cells of TCM, especially the signaling pathways. In addition, we also briefly discussed the relationship between gut microbiota and TCM and described the role of drug delivery systems for using TCM more accurately and safely. We provide updated and comprehensive insights into the clinical application of TCM for inflammatory arthritis treatment. We hope this review can guide and inspire researchers to further explore mechanisms of the anti-arthritis activity of TCM and make a great leap forward in comprehending the science of TCM.

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

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-1ß, 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.