Ca²⁺ signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats

Abstract

Background and Purpose Celastrol exhibits anti‐arthritic effects in rheumatoid arthritis (RA), but the role of celastrol‐mediated Ca 2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol‐induced Ca 2+ signalling in synovial fibroblasts of RA patients and adjuvant‐induced arthritis (AIA) in rats. Experimental Approach We used computational docking, Ca 2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS), mechanisms of Ca 2+ ‐mediated autophagy were analysed by histological, immunohistochemical and flow cytometric techniques. Anti‐arthritic effects of celastrol, autophagy induction, and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes, using siRNA methods to study calmodulin, calpains, and calcineurin. Key Results Celastrol inhibited SERCA to induce autophagy‐dependent cytotoxicity in RASFs/RAFLS via Ca 2+ /calmodulin‐dependent kinase kinase‐β–AMP‐activated protein kinase–mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory‐ and autoimmunity‐associated genes down‐regulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca 2+ in celastrol‐regulated gene expression. Conclusion and Implications Celastrol triggered Ca 2+ signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium‐dependent/‐binding proteins facilitating the exploitation of anti‐arthritic drugs based on manipulation of Ca 2+ signalling.

Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis

“…Many studies showed the Tripterygium ingredients have the properties to promote FLS apoptosis and cell cycle arrest and inhibit FLS autophagy ( Xu, 2013 ; Xu et al., 2013 ; Lei et al., 2015 ; Su et al., 2017 ; Wong et al., 2019 ). It may be relevant to the increased expression of Bax/Bcl-2, Caspase-3, Caspase-9, and regulating by Ca2+/calmodulin-dependent protein kinases beta (CaMKK)-AMPK-mTOR signaling pathway.…”

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

“…Medicine have become important choices for the treatment of several chronic diseases, including liver fibrosis. 5,7 Celastrol is a pentacyclic triterpenoid compound 8,9 (the chemical structure of celastrol is shown in Figure 1), which is isolated from a common clinical used Traditional Chinese Medicine named Tripterygium wilfordii Hook F.…”

“…The active ingredients extracted from Traditional Chinese Medicine have become important choices for the treatment of several chronic diseases, including liver fibrosis . Celastrol is a pentacyclic triterpenoid compound (the chemical structure of celastrol is shown in Figure ), which is isolated from a common clinical used Traditional Chinese Medicine named Tripterygium wilfordii Hook F. Celastrol possesses multiple pharmacological effects and showed potent anti‐inflammatory effect against many disease models, and however, few reports can be seen regarding the anti‐inflammatory potential of celastrol in liver fibrosis. SIR2 is a family of histone deacetylases and is widely distributed in cells with multiple functions .…”

The expression of TwDXS in the MEP pathway specifically affects the accumulation of triptolide

“…Modern research shows that triptolide has antitumor, anti‐cystogenesis, anti‐inflammatory and immunosuppressive activities, with applications in cancer treatment (Titov et al , Zhou et al , , Liu et al ). Celastrol, a red triterpenoid, shows effects against obesity (Fang et al ) and rheumatoid arthritis (Wong et al ).…”