YAP/TAZ: Key Players for Rheumatoid Arthritis Severity by Driving Fibroblast Like Synoviocytes Phenotype and Fibro-Inflammatory Response

Abstract

ObjectiveThe role of YAP/TAZ, two transcriptional co-activators involved in several cancers, was investigated in rheumatoid arthritis (RA).MethodsFibroblast like synoviocytes (FLS) from patients with RA or osteoarthritis were cultured in 2D or into 3D synovial organoids. Arthritis rat model (n=28) and colitis mouse model (n=21) were used. YAP/TAZ transcriptional activity was inhibited by verteporfin (VP). Multiple techniques were used to assess gene and/or protein expression and/or localization, cell phenotype (invasion, proliferation, apoptosis), bone erosion, and synovial stiffness.ResultsYAP/TAZ were transcriptionally active in arthritis (19-fold increase for CTGF expression, a YAP target gene, in RA vs. OA organoids; p<0.05). Stiff support of culture or pro-inflammatory cytokines further enhanced YAP/TAZ transcriptional activity in RA FLS. Inhibiting YAP/TAZ transcriptional activity with VP restored a common phenotype in RA FLS with a decrease in apoptosis resistance, proliferation, invasion, and inflammatory response. Consequently, VP blunted hyperplasic lining layer formation in RA synovial organoids. In vivo, VP treatment strongly reduced arthritis severity (mean arthritic index at 3.1 in arthritic group vs. 2.0 in VP treated group; p<0.01) by restoring synovial homeostasis and decreasing systemic inflammation. YAP/TAZ transcriptional activity also enhanced synovial membrane stiffening in vivo, thus creating a vicious loop with the maintenance of YAP/TAZ activation over time in FLS. YAP/TAZ inhibition was also effective in another inflammatory model of mouse colitis.ConclusionOur work reveals that YAP/TAZ were critical factors during arthritis. Thus, their transcriptional inhibition could be relevant to treat inflammatory related diseases.

YAP Transcriptional Activity Dictates Cell Response to TNF In Vitro

“…However, the role of YAP for NF-κB activity is also controversial in the literature. Our work is in line with the work of others showing that YAP transcriptional activity could increase NF-κB signaling ( 33 , 34 , 48 – 50 ). On the opposite, strong evidence highlighted that YAP could inhibit NF-κB activity by interacting with and blocking upstream NF-κB signaling members such as TAK1 and TRAF6 leading to NF-κB retention in the cytoplasm ( 35 , 38 ).…”

“…Moreover, YAP was shown to be partially activated by Rho family of GTPases signaling in response to TNF in endothelial cells ( 32 ). TNF activates YAP in breast cancer cells ( 33 ), endothelial cells ( 32 ) and synovial cells ( 34 ). On the opposite, 1 and 6 h of TNF administration lead to YAP transcriptional activity decrease both in chondrocytes and in HEK293 cell ( 35 , 36 ).…”

Improvement of Pain Management by Nefopam in a Rat Adjuvant-Induced Arthritis Model

“…The adjuvant-induced arthritis (AIA) is a well-known model used to investigate arthritic diseases for their pathophysiologic similarities to human arthritis. This model is widely used to investigate arthritic diseases ( 1 – 3 ). This is a robust model with rapid arthritis onset, high arthritis prevalence, and easy clinical measurements ( 4 ).…”

Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis

“…YAP and TAZ share structure similarity and have overlapped functions; both exert their transcriptional activity via translocation to the nucleus and by interaction with transcriptional enhanced associate domains (TEAD). YAP/TAZ transcriptional activity is enhanced in RA fibroblasts to promote their proliferation and invasive behavior ( 71 , 72 ). In vitro , blocking YAP/TAZ activity using verteporfin, which inhibits YAP/TAZ binding to TEAD, resulted in reduced RA fibroblast resistance to apoptosis, diminished proliferation, less invasion, and poor inflammatory response ( 72 ).…”

“…YAP/TAZ transcriptional activity is enhanced in RA fibroblasts to promote their proliferation and invasive behavior ( 71 , 72 ). In vitro , blocking YAP/TAZ activity using verteporfin, which inhibits YAP/TAZ binding to TEAD, resulted in reduced RA fibroblast resistance to apoptosis, diminished proliferation, less invasion, and poor inflammatory response ( 72 ). Moreover, in organoid culture system, verteporfin was able to prevent RA fibroblasts to form synovial lining layer and interrupt already formed lining layer.…”