Anti-Inflammatory Effect of Geniposide on Osteoarthritis by Suppressing the Activation of p38 MAPK Signaling Pathway

Abstract

It has been suggested that the activation of the p38 mitogen activated protein kinases (MAPKs) signaling pathway plays a significant role in the progression of OA by leading to the overexpression of proinflammatory cytokines, chemokines, and signaling enzymes in human osteoarthritis chondrocytes. However, most p38 MAPK inhibitors applied for OA have been thought to be limited due to their potential long-term toxicities. Geniposide (GE), an iridoid glycoside purified from the fruit of the herb, has been widely used in traditional medicine for the treatment of a variety of chronic inflammatory diseases. In this study, we evaluated the inhibition effect of geniposide on the inflammatory progression of the surgically induced osteoarthritis and whether the protective effect of geniposide on OA is related to the inhibition of the p38 MAPK signaling pathway. In vitro, geniposide attenuated the expression of inflammatory cytokines including interleukin-1 (IL-1), tumor necrosis factor (TNF-α), and nitric oxide (NO) production as well as matrix metalloproteinase- (MMP-) 13 in chondrocytes isolated from surgically induced rabbit osteoarthritis model. Additionally, geniposide markedly suppressed the expression of IL-1, TNF-α, NO, and MMP-13 in the synovial fluid from the rabbits with osteoarthritis. More importantly, our results clearly demonstrated that the inhibitory effect of geniposide on surgery-induced expression of inflammatory mediators in osteoarthritis was closely associated with the suppression of the p38 MAPK signaling pathways. Our study demonstrates that geniposide may have therapeutic potential to serve as an alternative agent for the p38 MAPK inhibition for the treatment of OA due to its inherent features of biological activities and low toxicity as a traditional Chinese medicine.

Molecular Mechanisms Involved in Oxidative Stress-Associated Liver Injury Induced by Chinese Herbal Medicine: An Experimental Evidence-Based Literature Review and Network Pharmacology Study

“…Geniposide, an iridoid glycoside in Gardenia jasminoides , exerts anti-fibrotic, anti-osteoarthritis, and anti-epilepsy actions by modulation of the expression of transforming growth factor-β (TGF-β)/Smad4, p38 mitogen-activated protein kinase (p38 MAPK), and PI3K/Akt/GSK-3beta signaling pathways, respectively [ 55 , 56 , 57 ]. Whereas, geniposide manifested a number of pathological phenomena in the liver of SD rat with the dose greater than 574 mg/kg, such as elevated MDA, liver enzymes (ALT, AST, alkaline phosphatase (ALP), total bilirubin), focal necrosis, and downregulated SOD, leading to the onset of oxidative stress caused hepatotoxicity [ 58 ].…”

Identification and functional analysis of long non‐coding RNAs in the synovial membrane of osteoarthritis patients

“…According to the KEGG pathway analysis, coexpressed genes in the green module mainly participate in the TNF, IL‐17, NOD‐like receptor, and MAPK signalling pathways. These pathways are mainly involved in inflammation and the progression of OA . The MAPK signalling pathway, one of intracellular serine‐threonine protein kinase superfamily members, is the centre of multiple signal transduction pathways .…”

“…The MAPK signalling pathway, one of intracellular serine‐threonine protein kinase superfamily members, is the centre of multiple signal transduction pathways . It has been suggested that the MAPK pathway activation results in the overexpression of proinflammatory cytokines, chemokines, and signalling enzymes in human OA chondrocytes, which play a significant role in the progression of OA . Blockage or inhibition of the activation of MAPK signalling can inhibit inflammatory cytokine production in OA chondrocytes to prevent the degradation of bone and cartilage .…”

Unraveling Natural Products’ Role in Osteoarthritis Management—An Overview

“…Geniposide (Scheme 4), an iridoid glycoside purified from fruits (most well-known Gardenia jasminoides) and herbs, has been commonly used in folk medicine for many chronic inflammatory conditions [92,93]. A 2018 study by Chen et al demonstrated that in the context of a surgically-induced OA rabbit model, this compound effectively suppressed IL-1, TNF-α, NO, and MMP-13 expression in animals synovial fluid [99]. Similar in vitro and in vivo results were obtained by Pan T. et al as the intervention promoted the production of collagen II and decreased the expression of proapoptotic molecules-Bax, Cyto-c, C-caspase 3-as opposed to an increasing Bcl-2 expression [100].…”