Oroxylin A attenuates IL‑1β‑induced inflammatory reaction via inhibiting the activation of the ERK and PI3K/AKT signaling pathways in osteoarthritis chondrocytes

Abstract

Osteoarthritis (OA) is characterized by degradation of the articular cartilage, synovium inflammation, subchondral bone sclerosis and osteophyte formation. OA is the most common degenerative joint disorder among the elderly population. In particular, currently available therapeutic strategies, such as non-steroidal anti-inflammatory drugs (NSAIDs) may cause severe side-effects. Therefore, novel candidate targets for OA therapy are urgently needed. Oroxylin A (OrA) is a natural mono-flavonoid that can be extracted from Scutellariae radix. The present study aimed to investigate the potential effects of OrA on interleukin (IL)-1β-induced chondrocytes inflammatory reactions. The current study performed quantitative PCR, western blotting and cell immunofluorescence to evaluate the effect of Oroxylin A in chondrocyte inflammation. The results demonstrated that OrA significantly attenuated the upregulation of inducible nitric oxide synthase and cyclooxygenase 2 by IL-1β at both protein and mRNA levels. IL-1β-stimulated upregulation of matrix metalloproteinase (MMP)-3 and MMP-13 expression, in addition to disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 expression, were all inhibited by OrA. Treatment with OrA significantly reversed the degradation of type II collagen and aggrecan by IL-1β. Mechanistically, OrA suppressed the IL-1β induced activation of ERK1/2 and PI3K/AKT signaling pathways. In conclusion, these findings suggest that OrA can serve as a potential therapeutic agent for the treatment of OA.

ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells

“…Studies also revealed that the PI3K/AKT/mTOR pathway plays a crucial role in cartilage degradation and can be used as a therapeutic target for the clinical intervention of OA (41,42). Consistently, we identified the signaling proteins that are enriched in PI3K/AKT pathway (Figure S2) and the perturbagens that inhibit the PI3K/AKT signaling pathway, including oroxylin A (43), KU-0063794 (44), and other novel perturbagens such as NVP-BEZ235 and TG100-115 (Table S4). In addition, previous reports have indicated that VEGF can be a biomarker for patients with OA, which is highly expressed in articular cartilage, synovium, subchondral bone and serum of OA patients (45).…”

4-Methylumbelliferone suppresses catabolic activation in anterior cruciate ligament-derived cells via a mechanism independent of hyaluronan inhibition

“…Previous studies reported the inhibition of AKT activation by 4-MU in cancer cell line, such as prostate cancer [ 37 ], osteosarcoma [ 38 ], and breast cancer [ 39 ]. Recent study reported that MMP-3 and -13 was induced by IL-1β via PI3K/AKT signaling pathways in chondrocytes [ 40 ]. In tumor cells, PI3K/Akt signaling pathway is reported to involve cell proliferation and apoptosis via CD44/HA interaction [ 41 ].…”

Oroxylin A: A Promising Flavonoid for Prevention and Treatment of Chronic Diseases

“…For instance, OA inhibited the expression of several pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β, IL-4, IL-6, IL-13) [ 69 , 70 ]. Apart from these, OA was also shown to reduce the expression of enzymes, including cyclooxygenase 2 (cox-2), inducible nitric oxide synthase (iNOS), glycogen synthase kinase 3-β (GSK-β), lactate dehydrogenase (LDH), pyruvate kinases isozymes (PKM1/PKM2), etc., which envisages its anti-inflammatory properties [ 71 , 72 ].…”

“…Besides, OA attenuated IL-1β-stimulated upregulation of MMP-3 and MMP-13 expression, disintegrin, and matrix metalloproteinase with thrombospondin motifs, ADAMTS-4 and ADAMTS-5 expression. Furthermore, OA suppressed the activation of ERK 1/2 and PI3K/Akt signaling pathways and caused the reversal of IL-1β-induced type II collagen and aggrecan degradation [ 72 ]. Both studies suggest that OA could be a potential therapeutic agent for osteoarthritis.…”