Journal Article

Deletion of activin A in mesenchymal but not myeloid cells ameliorates disease severity in experimental arthritis

Reinhardt, Julia, Dankbar, Berno, Wehmeyer, Corinna, Fennen, Michelle, Pap, Thomas, Werbenko, Eugenie, Geers, Fabienne, Dienstbier, Mike, Paruzel, Peter, Korb-Pap, Adelheid, Waltereit-Kracke, Vanessa, Intemann, Johanna, Beckmann, Denise

2022

Overview

ObjectiveThe aim of this study was to assess the extent and the mechanism by which activin A contributes to progressive joint destruction in experimental arthritis and which activin A-expressing cell type is important for disease progression.MethodsLevels of activin A in synovial tissues were evaluated by immunohistochemistry, cell-specific expression and secretion by PCR and ELISA, respectively. Osteoclast (OC) formation was assessed by tartrat-resistant acid phosphatase (TRAP) staining and activity by resorption assay. Quantitative assessment of joint inflammation and bone destruction was performed by histological and micro-CT analysis. Immunoblotting was applied for evaluation of signalling pathways.ResultsIn this study, we demonstrate that fibroblast-like synoviocytes (FLS) are the main producers of activin A in arthritic joints. Most significantly, we show for the first time that deficiency of activin A in arthritic FLS (ActβAd/d ColVI-Cre) but not in myeloid cells (ActβAd/d LysM-Cre) reduces OC development in vitro, indicating that activin A promotes osteoclastogenesis in a paracrine manner. Mechanistically, activin A enhanced OC formation and activity by promoting the interaction of activated Smad2 with NFATc1, the key transcription factor of osteoclastogenesis. Consistently, ActβAd/d LysM-Cre hTNFtg mice did not show reduced disease severity, whereas deficiency of activin A in ColVI-Cre-expressing cells such as FLS highly diminished joint destruction reflected by less inflammation and less bone destruction.ConclusionsThe results highly suggest that FLS-derived activin A plays a crucial paracrine role in inflammatory joint destruction and may be a promising target for treating inflammatory disorders associated with OC formation and bone destruction like rheumatoid arthritis.

• Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited,BMJ Publishing Group
• Subject: Acid phosphatase / Activin / Activins - genetics / Animals / Arthritis, Experimental - pathology / arthritis, rheumatoid / Bone growth / Bone resorption / Calcium phosphates / Cell division / Computed tomography / Cytokines / Disease / Enzyme-linked immunosorbent assay / Fibroblasts / Fibroblasts - metabolism / Immunoblotting / Immunohistochemistry / Inflammation / Inflammation - pathology / Inflammatory diseases / Joint diseases / Mesenchyme / Mice / Myeloid cells / Osteoarthritis / Osteoclastogenesis / Paracrine signalling / Pathology / Rheumatoid Arthritis / Severity of Illness Index / Signal transduction / Smad2 protein / Synovial Membrane - metabolism / Synoviocytes / Synoviocytes - metabolism / Tumor necrosis factor-TNF