Abstract
The inflammatory environment is correlated with extracellular matrix (ECM) degradation and chondrocyte hypertrophy in the development of osteoarthritis (OA). Previous studies have reported the anti-inflammatory effects of wogonoside in several diseases. In the present study, we investigated the protective effects of wogonoside in relation to the development of OA and delineated the potential mechanism. In vitro, wogonoside decreased the production of pro-inflammatory cytokines like Nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). It also inhibited the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both at gene and protein levels. Wogonoside also inhibited hypertrophy and the generation of vascular endothelial growth factor (VEGF) in interleukin-1β (IL-1β)-induced chondrocytes. Moreover, wogonoside promoted the expression of anabolic factors Sox-9, type two collagen and aggrecan while inhibiting the expression of catabolic factors such as matrix metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS-5) in mouse chondrocytes. Mechanistically, we found that wogonoside inhibited nuclear factor kappa B/ hypoxia-inducible factor two alpha (NF-κB/HIF-2α) activation via the phosphatidylinositol 3 kinase (PI3K) /AKT pathway. The protective effects of wogonoside were also observed in vivo and the pharmacokinetic results of wogonoside indicated that good systemic exposure was achievable after oral administration of wogonoside. In conclusion, our stduy demonstrates that wogonoside attenuates IL-1β-induced ECM degradation and hypertrophy in mouse chondrocytes via suppressing the activation of NF-κB/HIF-2α by the PI3K/AKT pathway. Moreover, wogonoside ameliorates OA progression in vivo, indicating that wogonoside may serve as a promising therapeutic agent for the treatment of OA.
Highlights
Osteoarthritis (OA), a painful degenerative joint disease characterized by articular cartilage loss, subchondral bone remodeling and inflammation of the synovium, causes progressive disabilities in the elderly due to its irreversible outcomes [1, 2]
The cytotoxic effects of wogonoside on chondrocytes was determined at various concentrations (12.5, 25, 50, 100, and 200 μM) for 24 and 48 h using the Cell Counting Kit-8 (CCK8) assay
We determined whether wogonoside inhibits inducible nitric oxide synthase (iNOS) and COX-2 production at the transcriptional and/ or translational level using real-time polymerase chain reaction (RT-PCR) and Western blot analysis
Summary
Osteoarthritis (OA), a painful degenerative joint disease characterized by articular cartilage loss, subchondral bone remodeling and inflammation of the synovium, causes progressive disabilities in the elderly due to its irreversible outcomes [1, 2]. There is a general consensus that inflammation plays an important role in the OA process, contributing to the shift of chondrocyte phenotype and degradation of the ECM [8,9,10] Inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 and tumor necrosis factoralpha (TNF-α) produced by activated synoviocytes, mononuclear cells or by articular cartilage itself are strongly related to the pathophysiology of osteoarthritis [11]. Among these cytokines, the IL-1β exert its inflammatory effects by significantly increasing the secretion of pro-inflammatory factors and catabolic factors such as prostaglandin E2 (PGE2), nitric oxide (NO), thrombospondin motifs (ADAMTS), and matrix metalloproteinases (MMPs) to destroy the ECM [12,13,14]. OA chondrocytes are unable to sustain cartilage homeostasis and fail to replace components of the ECM, collagen
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