Gingko biloba-inspired lactone prevents osteoarthritis by activating the AMPK-SIRT1 signaling pathway

Abstract

Background Uncoupled extracellular matrix (ECM) causes cartilage degeneration and osteoarthritis (OA) by suppressing the synthesis and activating the degradation of ECM components. Gingko biloba is a natural Chinese herb with a variety of biological functions; however, the extent to which it can protect against OA and the mechanisms involved are unknown. Methods In our study, using bioinformatics tools, we were able to identify an important lactone, bilobalide (BB), from Gingko biloba. In vitro experiments were performed to evaluate the potential therapeutic effects of BB on ECM homeostasis. In vivo experiments were conducted to assess the protection of systemic administration of BB on cartilage degeneration. Molecular mechanisms underlying BB-regulated anti-arthritic role were further explored. Results In interleukin-1β-incubated human chondrocytes, in vitro treatment with BB increased the expression of cartilage anabolic proteins, while inhibiting the activities of ECM degrading enzymes. In a mice model, systemic administration of BB, in vivo, prevented post-traumatic cartilage erosion and attenuated the formation of abnormal osteophytes in the subchondral bone. Mechanistically, the activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK)-sirtuin 1 (SIRT1) signaling pathway was involved in the anti-arthritic effects of BB. In vitro, blocking BB’s chondroprotection with the AMPK-specific inhibitor Compound C abrogated it. Conclusions These results demonstrated that BB extracted from Gingko biloba regulates ECM balance to prevent OA by activating the AMPK-SIRT1 signaling pathway. This study proposed the monomer BB, a traditional Chinese medicine, as a de novo therapeutic insight for OA. Graphical Abstract Schematic representation of the experimental design. Based on the bioinformatic analysis, bilobalide (BB), a natural herb Gingko biloba-derived ingredient, was identified as a candidate for treating osteoarthritis. In vitro, BB treatment not only facilitates cartilage extracellular matrix synthesis but also inhibits proteolytic enzyme activities. In vivo intraperitoneal injection of BB improves cartilage degeneration and subchondral bone sclerosis. BB, in particular, had anti-arthritic effects by activating the AMPK-SIRT1 signaling pathway.

Anti-Inflammatory and Chondroprotective Effects Induced by Phenolic Compounds from Onion Waste Extracts in ATDC-5 Chondrogenic Cell Line

“…Phenolic compounds and specifically flavonoids have been widely reported as efficient inhibitors of catabolic processes in chondrocytes depleting the expression of characteristic molecular markers such as NO, iNOS, MMP-3, MMP-13, ADAMTS-4, IL-1β, IL-6, and IL-8, among others [ 7 ]. The anti-inflammatory effects of these compounds have a great impact on ECM degradation processes owing to their capability to alleviate the inhibition of matrix synthesis and the activation of proteinases activity [ 16 ]. Our studies have focused on these effects to evaluate the potential of OE in the protection of chondrocytes from inflammation and degeneration.…”

“…Several studies have emphasized the relevant role of different antioxidant and anti-inflammatory compounds in alleviating cartilage damage [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In this regard, the search for novel products with antioxidant and anti-inflammatory abilities is appealing to develop more effective strategies in OA treatment.…”

Natural products in osteoarthritis treatment: bridging basic research to clinical applications

“…Terpenoids. Bilobalide, extracted from Gingko biloba, promoted extracellular matrix synthesis and inhibited proteolytic enzyme activities through activation of the AMPK-SIRT1 pathway [122]. 2.…”