Abstract
BackgroundCartilage degradation would result in osteoarthritis (OA). p16INK4awas found in some age-related diseases. In this study, we aimed to determine the role of p16INK4a during OA and to investigate the underlying mechanisms.MethodsEnzyme-linked immunosorbent assay (ELISA) was performed to test the activity of senescence-associated secretory phenotype (SASP). Real-time PCR (RT-PCR) and Western blot were used to determine the expressions of target genes.ResultsThe increased expressions of p16INK4a and E2F2 were accompanied with cartilage degradation induced by IL-1β. Over-expression of p16INK4a enhanced the secretion of SASP markers (TGFβ, IL-6, IL-8, IL-1α, MMP3 and MMP13), reduced the expression of type II procollagen (COL2A1).Thus, the over-expression of p16INK4a lead to cartilage injury. Moreover, we found that the expression of E2F2 was enhanced in p16INK4a over-expression group, and that cartilage injury caused by p16INK4a was alleviated by depleting E2F2.Conclusionsp16INK4a was up-regulated during the cartilage injury in OA. p16INK4a promoted cartilage injury by increasing the expression of E2F2. Thus, this study extends the molecular regulation network for understanding pathological progression of OA, and provides potential therapeutic target for OA.
Highlights
Cartilage degradation would result in osteoarthritis (OA). p16INK4awas found in some age-related diseases
The results showed that over-expression of p16INK4a enhanced the secretion of TGFβ, IL-6, IL-8, IL-1α, MMP3 and MMP13 (Fig. 3a), and that the expression of Col2A1 was reduced by over-expression of p16INK4a
In summary, this study demonstrated that over-expression of p16INK4a promoted cartilage injury
Summary
Cartilage degradation would result in osteoarthritis (OA). p16INK4awas found in some age-related diseases. We aimed to determine the role of p16INK4a during OA and to investigate the underlying mechanisms. Osteoarthritis (OA) is one of the most common chronic diseases among aged population [1, 2]. During the process of aging, senescence-associated secretory phenotype (SASP), which includes growth factors (such as TNF-β), pro-inflammatory cytokines (such as IL-6, IL-8, IL-1α) and matrix remodeling regulatory metalloproteases (such as MMP1 and MMP13) [6], expressed highly. The transcript of p16INK4a derives from alternative splicing of INK4a/ARF [14]. By binding to CDK4 and CDK6 and repressing phosphorylation of pRb, p16INK4a is well known as a cell cycle regulator [15]. The increased expression of p16INK4a is often accompanied
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