Abstract
BackgroundThe Cadherin-11 and PI3K/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis. The study aimed to investigate the role of PI3K/Akt signaling pathway in the expression of Cadherin-11 and migration and invasive capacity of fibroblast-like synoviocytes (FLS) of OA patients under stimulation of TNF-α and to explore the effect of the PI3K/Akt inhibitor and Cadherin-11 antibody in the therapy of the collagenase-induced osteoarthritis (CIOA) mice.MethodsFLS were primarily cultured from synovium of osteoarthritic patients during total knee arthroplasty. Under the simulation of TNF-α, with or without PI3K/Akt inhibitor LY294002, Cadherin-11 expression was detected by real-time PCR and Western blot, as well as the migration and invasive capacity changes of OA FLS. Cadherin-11 antibody was injected intraarticularly or LY294002 was injected intraperitoneally in CIOA mice to evaluate the changes of synovitis score, cartilage damage, and Cadherin-11 expression.ResultsTNF-α stimulation increased Cadherin-11 expression at mRNA and protein level in OA FLS and also increased the phosphorylation-dependent activation of Akt. PI3K inhibitor LY294002 attenuated TNF-α-induced overexpression of Cadherin-11 and decreased the invasive capacity of OA FLS. Intraperitoneal injection of PI3K inhibitor LY294002 could decrease the Cadherin-11 protein expression in synovium of CIOA mice, although it has no significant inhibitory effect on synovitis and cartilage damage. Intraarticular injection of Cadherin-11 antibody attenuated the synovitis and cartilage damage in the CIOA joints and decreased Cadherin-11 expression in the synovial lining.ConclusionsPI3K/Akt pathway was associated with TNF-α-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. Anti-Cadherin-11 therapy in CIOA mice could attenuate the pathological changes of OA joints.
Highlights
The Cadherin-11 and Phosphatidylinositol 3-kinase (PI3K)/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis
Cadherin-11 upregulation by TNF-α was associated with PI3K/Akt pathway Cadherin-11 was increased at mRNA and protein level in OA fibroblast-like synoviocytes (FLS) with TNF-α stimulation compared to the control group (Fig. 1a, b)
Cadherin-11 immunostaining of synovium in collagenase-induced osteoarthritis (CIOA) mice with or without PI3K inhibitor, LY294002. a PI3K inhibitor, LY294002, significantly decreased expression of Caherin-11 in synovial lining layer (f, p < 0.01) and sublining layer (g, p < 0.05) of CIOA mice; it has no obvious effect on synovial hyperplasia, inflammatory infiltration, and density of synovial stromal cells (b, c, d, p < 0.05) as well as the total synovitis score (e, p > 0.05) (n = 6 per group respectively; data presented as mean ± Standard error of the mean (SEM); Kruskal–Wallis test followed by Mann–Whitney U test, *p < 0.05, **p < 0.01, ***p < 0.001)
Summary
The Cadherin-11 and PI3K/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis. The study aimed to investigate the role of PI3K/Akt signaling pathway in the expression of Cadherin-11 and migration and invasive capacity of fibroblast-like synoviocytes (FLS) of OA patients under stimulation of TNF-α and to explore the effect of the PI3K/Akt inhibitor and Cadherin-11 antibody in the therapy of the collagenase-induced osteoarthritis (CIOA) mice. Cadherin-11 is a classical molecule that mediates hemophilic cell-to-cell adhesion in FLS, plays an important role in the development of the normal synovium lining layer of the joint [9,10,11], and has been identified to participate in the cartilage invasion except for its adhesive function [10]. The underlying mechanism for the upregulation of Cadherin-11 expression in FLS by the stimulation of TNF-α was rarely investigated
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