Abstract
Osteoarthritis (OA) is a common joint disorder with varying degrees of inflammation. The ideal anti-OA drug should have immunomodulatory effects while at the same time having limited or no toxicity. We examined the anti-inflammatory effects of Ginkgo biloba extract (EGb) in interleukin-1 (IL-1)-stimulated human chondrocytes. Chondrocytes were prepared from cartilage specimens taken from patients with osteoarthritis who had received total hip or total knee replacement. The concentrations of chemokines and the degree of cell migration were determined by ELISA and chemotaxis assays, respectively. The activation of inducible nitric oxide synthase (iNOS), mitogen-activated protein kinases (MAPKs), activator protein-1 (AP-1), and nuclear factor-kappaB (NF-κB) was determined by immunoblotting, immunohistochemistry, and electrophoretic mobility shift assay. We found that EGb inhibited IL-1-induced production of chemokines, which in turn resulted in attenuation of THP-1 cell migration toward EGb-treated cell culture medium. EGb also suppressed IL-1-stimulated iNOS expression and release of nitric oxide (NO). The EGb-mediated suppression of the iNOS-NO pathway correlated with the attenuation of activator protein-1 (AP-1) but not nuclear factor-kappaB (NF-κB) DNA-binding activity. Of the mitogen-activated protein kinases (MAPKs), EGb inhibited only c-Jun N-terminal kinase (JNK). Unexpectedly, EGb selectively caused degradation of c-Jun protein. Further investigation revealed that EGb-mediated c-Jun degradation was preceded by ubiquitination of c-Jun and could be prevented by the proteosome inhibitor MG-132. The results imply that EGb protects against chondrocyte degeneration by inhibiting JNK activation and inducing ubiquitination-dependent c-Jun degradation. Although additional research is needed, our results suggest that EGb is a potential therapeutic agent for the treatment of OA.
Highlights
Osteoarthritis (OA) is a common joint disorder among people of advanced age
We found that EGb elicits an immunomodulatory effect by inhibiting IL-1-induced Jun N-terminal kinase (JNK) activation and degrading c-Jun protein in a ubiquitination-dependent manner in human chondrocytes
We examined the effects of EGb on IL-1-induced chemokine production in human chondrocytes
Summary
In addition to subchondral bone and synovial membrane, cartilage is recognized as one of the main targeted structures responsible for joint diseases in OA patients. Cartilage damage results from the failure of chondrocytes to maintain a homeostatic balance between matrix synthesis and degradation. In this regard, inflammation plays a pivotal role in cartilage damage and the pathogenesis of OA [1]. Interleukin (IL)-1, a well-known cytokine that plays a critical role in the immunopathogenesis of OA, is responsible for damaging cartilage by inducing matrix metalloproteinases (MMPs) and proteases [3]. Blocking IL-1-induced MMP gene expression by physiologic and pharmacologic inhibitors has been reported to be an important therapeutic approach for OA patients [1]
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