Loss of Smad7 Promotes Inflammation in Rheumatoid Arthritis

Abstract

Objective: Smad7 is an inhibitory Smad and plays a protective role in many inflammatory diseases. However, the roles of Smad7 in rheumatoid arthritis (RA) remain unexplored, which were investigated in this study.Methods: The activation of TGF-β/Smad signaling was examined in synovial tissues of patients with RA. The functional roles and mechanisms of Smad7 in RA were determined in a mouse model of collagen-induced arthritis (CIA) in Smad7 wild-type (WT) and knockout (KO) CD-1 mice, a strain resistant to autoimmune arthritis induction.Results: TGF-β/Smad3 signaling was markedly activated in synovial tissues of patients with RA, which was associated with the loss of Smad7, and enhanced Th17 and Th1 immune response. The potential roles of Smad7 in RA were further investigated in a mouse model of CIA in Smad7 WT/KO CD-1 mice. As expected, Smad7-WT CD-1 mice did not develop CIA. Surprisingly, CD-1 mice with Smad7 deficiency developed severe arthritis including severe joint swelling, synovial hyperplasia, cartilage damage, massive infiltration of CD3+ T cells and F4/80+ macrophages, and upregulation of proinflammatory cytokines IL-1β, TNFα, and MCP-1. Further studies revealed that enhanced arthritis in Smad7 KO CD-1 mice was associated with increased Th1, Th2 and, importantly, Th17 over the Treg immune response with overactive TGF-β/Smad3 and proinflammatory IL-6 signaling in the joint tissues.Conclusions: Smad7 deficiency increases the susceptibility to autoimmune arthritis in CD-1 mice. Enhanced TGF-β/Smad3-IL-6 signaling and Th17 immune response may be a mechanism through which disrupted Smad7 causes autoimmune arthritis in CD-1 mice.

Organ Fibrosis and Autoimmunity: The Role of Inflammation in TGFβ-Dependent EMT

“…As clearly described in the paragraph describing TGF-β-mediated molecular pathways, TGF-β, through both type I and type II receptors, regulates TGF-β-responsive genes transcription by inducing the phosphorylation of Smad2 and Smad3 [ 76 , 80 , 146 ]. In addition, TGF-β induces Smad7 expression, which negatively regulates TGF-β/Smad signalling via a feedback inhibitory mechanism [ 92 ].…”

“…In addition, TGF-β induces Smad7 expression, which negatively regulates TGF-β/Smad signalling via a feedback inhibitory mechanism [ 92 ]. Based on these assumptions, in RA patients, the loss of inhibitory Smad7 was associated with a marked activation of TGFβ/Smad3 signalling and the development of arthritis [ 146 ]. Furthermore, in RA, not only did the inhibition of Smad7 promote TGFβ/Smad3 signalling and tissue fibrosis, but it also markedly enhanced NF-κB-driven inflammation [ 146 ].…”

“…Based on these assumptions, in RA patients, the loss of inhibitory Smad7 was associated with a marked activation of TGFβ/Smad3 signalling and the development of arthritis [ 146 ]. Furthermore, in RA, not only did the inhibition of Smad7 promote TGFβ/Smad3 signalling and tissue fibrosis, but it also markedly enhanced NF-κB-driven inflammation [ 146 ]. Supporting the protective and inhibitory role of Smad7 in tissue fibrosis and inflammation, the Smad7 deficiency observed in RA patients enhanced NF-κB signalling, Th1/Th17 differentiation, and synovial inflammation, probably through the hyperactivation of the TGF-β/Smad3-IL-6 molecular pathway, which is no longer controlled because of Smad7 inhibition [ 146 ].…”

Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems

“…Various studies revealed that TGF-β could persuade Smad2/3 phosphorylation to promote fibroblast differentiation ( Huang et al., 2019 ). It was also reported that, smad7 is an inhibitory Smad and plays a protective role in several inflammatory disorders by down regulating the phospho- smad3 ( Zhou et al., 2018 ). These evidences impelled us to focus on the impact of BCA on TGF-β/Smad signaling pathway.…”

Effect of Jiawei Fengshining on Synovial Cell Apoptosis and TGF-β1/Smad Signaling Pathway in Rats with Rheumatoid Arthritis

“…Xu et al found that abnormal activation of TGF-β causes articular subchondral bone destruction in the rheumatoid arthritis rat/ mouse models, and conditional deletion of TGF-βR2 in nestin-positive cells effectively halted progression of RA joint damage [37]. Zhou et al indicated that deletion of Smad7 promotes inflammation of rheumatoid arthritis [13]. Conversely, overexpression of Smad7 in the joint improves rheumatoid arthritis [38].…”