Deletion of activin A in mesenchymal but not myeloid cells ameliorates disease severity in experimental arthritis
Open Access
- 13 April 2022
- journal article
- research article
- Published by BMJ in Annals Of The Rheumatic Diseases
- Vol. 81 (8), 1106-1118
- https://doi.org/10.1136/annrheumdis-2021-221409
Abstract
Objective The 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. Methods Levels 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. Results In 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. Conclusions The 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.Funding Information
- German Research Foundation (INST 211/788-1)
This publication has 52 references indexed in Scilit:
- The Synovium in Rheumatoid ArthritisThe Open Rheumatology Journal, 2011
- Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markersBlood, 2011
- Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseasesThe Journal of Experimental Medicine, 2008
- Cytokines in the pathogenesis of rheumatoid arthritisNature Reviews Immunology, 2007
- Activin A Is an Essential Cofactor for Osteoclast InductionBiochemical and Biophysical Research Communications, 2000
- IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesisJCI Insight, 1999
- Immunohistochemical Detection of Activin A in OsteoclastsGerontology, 1996
- Functional analysis of activins during mammalian developmentNature, 1995
- Detection of Functional and Dimeric Activin A in Human Marrow MicroenvironmentAnnals of the New York Academy of Sciences, 1994
- Activin Enhances Osteoclast-like Cell Formation in VitroBiochemical and Biophysical Research Communications, 1993