Immune regulatory and anti‐resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice

• Published in: British journal of pharmacology 2024-12, Vol.181 (24), p.5009-5027
• Main Authors: Panwar, Preety, Andrault, Pierre Marie, Saha, Dipon, Brömme, Dieter
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Autoimmune diseases; Cathepsin K; Cathepsin K - antagonists & inhibitors; Cathepsin K - metabolism; Cell culture; Collagen; Cytokines; Disease resistance; Flow cytometry; Helper cells; immune cells; Immunosuppressive agents; inflammation; Joint diseases; Lymphocytes T; Macrophages; Male; Mice; Mice, Inbred DBA; NF-kappa B - metabolism; NF‐κB pathway; Oligomerization; Osteoclasts; Osteoclasts - drug effects; Phenanthrenes - pharmacology; Phenanthrenes - therapeutic use; Phosphorylation; Remission; Rheumatoid arthritis; Tanshinones
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.17312

Background and Purpose Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual‐action inhibitor, possessing both anti‐inflammatory and anti‐resorptive properties, as a novel treatment for RA. Experimental Approach Therapeutic efficacy and mechanisms of ectosteric (tanshinone IIA sulfonate [T06]) and active site‐directed (odanacatib [ODN]) inhibitors of cathepsin K (CatK) were evaluated in RA mouse models. Pathology was assessed through biochemical analyses and histopathological examination. Flow cytometry analysis was performed to characterize immune cells. Anti‐inflammatory effects of T06 on nuclear factor kappa beta (NF‐κB) pathway were studied in macrophages. Key Results T06 effectively lowered the number of joint‐resident immune cells, accompanied by significantly reduced production of inflammatory cytokines and collagenolytic proteases. This also included the suppression of Th17 cells and IL‐17, resulting in the reduction of osteoclasts in arthritic joints and amplification of the overall anti‐resorptive effect of T06, which has been attributed to its selective inhibition of the collagenolytic activity of CatK by preventing its oligomerization. The anti‐inflammatory mechanism of T06 was based on blocking the phosphorylation of IκBα in the NF‐κB pathway, resulting in reduced activation and expression of inflammatory cytokines. In contrast, ODN had no effect on inflammation and disease progression and was limited to the inhibition of CatK. Conclusions The combined anti‐resorptive and anti‐inflammatory activities characterize T06 as a novel therapeutic agent for RA.