Abstract
Peritendinous tissue fibrosis which leads to poor tendon function is a worldwide clinical problem; however, its mechanism remains unclear. Transcription factor RelA/p65, an important subunit in the NF-κB complex, is known to have a critical role in many fibrotic diseases. Here, we show that RelA/p65 functions as a core fibrogenic regulator in tendon adhesion and that its inhibition exerts an anti-fibrogenic effect on peritendinous adhesion. We detected the upregulation of the NF-κB pathway in human tendon adhesion using a gene chip microarray assay and revealed the overexpression of p65 and extracellular matrix (ECM) proteins Collagen I, Collagen III, and α-smooth muscle actin (α-SMA) in human fibrotic tissues by immunohistochemistry and western blotting. We also found that in a rat model of tendon injury, p65 expression correlated with tendon adhesion, whereas its inhibition by small interfering (si)RNA prevented fibrous tissue formation and inflammatory reaction as evidenced by macroscopic, biomechanical, histological, immunohistochemical, and western blotting analyses. Furthermore, in cultured fibroblasts, p65-siRNA, p65-specific inhibitor, Helenalin and JSH23 suppressed cell proliferation and promoted apoptosis, whereas inhibiting the mRNA and protein expression of ECM components and cyclo-oxygenase-2, an inflammatory factor involved in tendon adhesion. Our findings indicate that p65 has a critical role in peritendinous tissue fibrosis and suggest that p65 knockdown may be a promising therapeutic approach to prevent tendon adhesion.
Highlights
Flexor tendon adhesion, which is the generation of fibrotic tissue between the tendon and the surrounding synovial sheath after injury, is a complicated clinical problem.[1]
A heat map depicting gene expression in normal and fibrotic tissues indicated that transcripts of six genes, NFKBIA, MYD88, GADD45B, RELB, CXCL2, and IL6 participating in Nuclear factor (NF)-κB signaling were significantly increased in fibrotic tissues (Figure 1b), which was confirmed by real-time PCR (Supplementary Figure 1)
These results were confirmed in a rat model of tendon injury, where p65 expression was increased in peritendinous fibrotic tissue in parallel with the upregulation of extracellular matrix (ECM) deposition and the level of pro-inflammatory factor COX-2
Summary
Flexor tendon adhesion, which is the generation of fibrotic tissue between the tendon and the surrounding synovial sheath after injury, is a complicated clinical problem.[1]. A number of concepts regarding flexor tendon healing have been suggested,[4] the mechanism of peritendinous tissue fibrosis has not been well defined.[2] despite numerous existing strategies to prevent fibrogenesis, an effective approach for the inhibition of tendon adhesion at the key points is still under development.[2,5,6,7]. Persistent inflammation is known to activate fibrogenesis and is considered a major trigger in many fibrotic diseases.[8,9,10]. Nuclear factor (NF)-κB, a key regulator of inflammation and cell survival,[11,12] has been reported to promote fibrogenesis in the liver and kidney.[13,14,15] Among the five subunits of the NF-κB complex, RelA/p65 is regarded as the crucial member of the canonical NF-κB pathway.[16] The role of p65 in fibrosis has been studied in many diseases.
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