RT Journal Article
SR Electronic
T1 Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 891
OP 902
DO 10.1136/annrheumdis-2021-220002
VO 80
IS 7
A1 Zihao Li
A1 Siwen Chen
A1 Haowen Cui
A1 Xiang Li
A1 Dongying Chen
A1 Wenjun Hao
A1 Jianru Wang
A1 Zemin Li
A1 Zhaomin Zheng
A1 Zhongping Zhang
A1 Hui Liu
YR 2021
UL http://ard.bmj.com/content/80/7/891.abstract
AB Objectives The aim of this study was to identify the role of tenascin-C (TNC) in entheseal new bone formation and to explore the underlying molecular mechanism.Methods Ligament tissue samples were obtained from patients with ankylosing spondylitis (AS) during surgery. Collagen antibody-induced arthritis and DBA/1 models were established to observe entheseal new bone formation. TNC expression was determined by immunohistochemistry staining. Systemic inhibition or genetic ablation of TNC was performed in animal models. Mechanical properties of extracellular matrix (ECM) were measured by atomic force microscopy. Downstream pathway of TNC was analysed by RNA sequencing and confirmed with pharmacological modulation both in vitro and in vivo. Cellular source of TNC was analysed by single-cell RNA sequencing (scRNA-seq) and confirmed by immunofluorescence staining.Results TNC was aberrantly upregulated in ligament and entheseal tissues from patients with AS and animal models. TNC inhibition significantly suppressed entheseal new bone formation. Functional assays revealed that TNC promoted new bone formation by enhancing chondrogenic differentiation during endochondral ossification. Mechanistically, TNC suppressed the adhesion force of ECM, resulting in the activation of downstream Hippo/yes-associated protein signalling, which in turn increased the expression of chondrogenic genes. scRNA-seq and immunofluorescence staining further revealed that TNC was majorly secreted by fibroblast-specific protein-1 (FSP1)+fibroblasts in the entheseal inflammatory microenvironment.Conclusion Inflammation-induced aberrant expression of TNC by FSP1+fibroblasts promotes entheseal new bone formation by suppressing ECM adhesion forces and activating Hippo signalling.Data are available upon reasonable request. The data that support the findings in this study are available from the corresponding author upon request.