Abstract
Rheumatoid arthritis (RA) is a persistent autoimmune disease. Fibroblast-like synoviocytes (FLS) are a key component of invasive pannus and a pathogenetic mechanism in RA. Expression of bone morphogenetic protein 3 (BMP3) mRNA is reportedly decreased in the arthritic synovium. We previously showed that BMP3 expression is significantly downregulated in the synovial tissues of RA patients and models of adjuvant-induced arthritis (AIA). In the present study, we explored the association between BMP3 and FLS migration and secretion of proinflammatory factors in RA. We found that inhibition of BMP3 expression using BMP3 siRNA increased the proinflammatory chemokines and migration of FLS stimulated with TNF-α. Inhibition of BMP3 expression also increased expression of IL-6, IL-1β, IL-17A, CCL-2, CCL-3, VCAM-1, MMP-3, and MMP-9, but not TIMP-1, in AIA and RA FLS. Correspondingly, induction of BMP3 overexpression through intra-articular injection of ad-BMP3 diminished arthritis severity in AIA rats. We also found that BMP3 may inhibit activation of TGF-β1/Smad signaling. These data indicate that BMP3 may suppress the proliferation and migration of FLS via the TGF-β1/Smad signaling pathway.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and hyperplasia, pannus formation, and erosion of adjacent articular cartilage and bone leading to joint dysfunction [1, 2]
Immunofluorescence staining verified that bone morphogenetic protein 3 (BMP3) expression was notably decreased in RA synovial tissues (Figure 1C) and in RA fibroblast-like synoviocytes (FLS) treated with TNF-α (Figure 1D)
After RA FLS were treated with various inflammatory factors in vitro, such as IL-6, IL-1β, IL-17A, TNF-α, IFN-γ, and LPS, western blot results showed that BMP3 expression was decreased to different degrees (Figure 1F)
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and hyperplasia, pannus formation, and erosion of adjacent articular cartilage and bone leading to joint dysfunction [1, 2]. In RA, activated FLS invade the extracellular matrix and secrete proinflammatory factors [5], matrix metalloproteinases (MMPs) [6, 7], chemokines [8], and cell adhesion molecules [9], which destroy articular cartilage and bone and exacerbate joint dysfunction. Bone morphogenetic proteins (BMPs), as members of the TGF-β superfamily, are secreted signaling proteins [17]. They contribute to the development of cartilage and bone [18]. Accumulating evidence indicates that BMPs participate in regulating the inflammatory response, migration, and invasion of FLS [14, 16, 19]
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