Therapeutic potential of compound K as an IKK inhibitor with implications for osteoarthritis prevention: an in silico and in vitro study

Abstract

Ginsenosides have been used traditionally as an oriental medicine. However, the anti-osteoarthritic effect of ginsenoside compound K (hereafter referred to as CK) has not been reported. Therefore, in this study, the protective effects of CK were evaluated in silico and in vitro using HO-stimulated MC3T3-E1 cells by measuring the levels of proinflammatory cytokines responsible for articular cartilage degradation. In silico results demonstrated that, among the selected ginsenosides, CK is a non-toxic drug-like molecule with strong binding affinity for selected cytokine-activated kinase such as IkBα kinase (IKK). The molecular binding energy of CK with the active sites of IKK suggests anti-osteoarthritic functions. Cultured HO-stimulated MC3T3-E1 cells that were exposed to CK showed dramatically increased expression of osteoblast differentiation markers such as alkaline phosphatase (ALP) activity, type I collagen (Col-I) content, and mineralization. During aging, HO also leads to the production of reactive oxygen species (ROS) and nitric oxide (NO), which play important roles in the development of osteoarthritis (OA). Therefore, the effect of CK on ROS and NO generation was also examined. Our results showed that CK dose-dependently inhibited HO-induced ROS and NO production in MC3T3-E1 cells. Moreover, qRT-PCR data showed that CK increased expression of osteogenic markers such as ALP and Col-I but decreased expression of inflammatory-related genes including IKK and interleukin 1β (IL-1β) in a dose-dependent manner in HO-stimulated MC3T3-E1 cells. The findings of this study suggest the use of CK as a novel protective and therapeutic agent in AO.

Effects of ginsenosides on bone remodelling for novel drug applications: a review

“…Cultured H 2 O 2 stimulated MC3T3-E1 cells exposed to C-K showed a sharp increase in the expression of osteoblast differentiation markers, such as ALP activity, Col-1 content and mineralization. In addition, C-K reduced inflammation-related genes including IKK and interleukin 1β (IL-1β) expression [72]. Zhou et al [73] converted four compounds from ginsenoside Rb1, including C-K, compounds 2, 3, and 4.…”

Recent advance in treatment of osteoarthritis by bioactive components from herbal medicine

“…Shikonin inhibits chondrocyte inflammation by the regulation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway in OA rats [35]. Anti-inflammatory effects of licochalcone A are associated with NF-κB and nuclear [37]. Emodin ameliorates OA cartilage inflammation by inhibiting NF-κB and Wnt/β-catenin signaling [38,39].…”

“…In addition to osteoclasts, osteoblasts are also the major cellular component of bone, which synthesize dense and crosslinked collagen and reshape bone tissue. Magnoflorine [23] and compound K [37] stimulate osteoblast proliferation, differentiation, and mineralization. Resveratrol may play the roles on alkaline phosphatase activity, osteocalcin release, and mineralization in osteoblasts via promoting the Wnt/β-catenin signaling pathway [94].…”

“…Anti-inflammatory effects of licochalcone A are associated with NF-κB and nuclear factor (erythroid-derived 2)-like 2 signaling pathways [ 36 ]. Compound K, an IkBα kinase inhibitor, may alleviate inflammatory response in cartilage [ 37 ]. Emodin ameliorates OA cartilage inflammation by inhibiting NF-κB and Wnt/β-catenin signaling [ 38 , 39 ].…”

“…In OA chondrocytes, resveratrol may reverse the decrease in the levels of type II collagen, aggrecan, and glycosaminoglycan by regulating silent information regulator 2 type 1, hypoxia-inducible factor-2α, and MMPs expression [ 24 , 62 , 63 , 77 ]. Curcumin [ 28 ], naringin [ 42 ], icariin [ 16 , 78 , 79 ], berberine [ 68 , 69 ], sinomenine [ 72 ], tetramethylpyrazine [ 13 , 70 , 80 ], astragaloside IV [ 81 ], halofuginone [ 82 ], puerarin [ 83 ], quercetin [ 84 ], celastrol [ 54 , 85 ], harpagoside [ 32 ], ferulic acid [ 55 ], shikonin, acetylshikonin [ 86 ], ginsenoside Rb1 [ 76 , 87 ], cinnamophilin [ 30 ], honokiol [ 50 ], 2, 3, 5, 4′-tetrahydroxystilbene-2-O-β-d-glucoside [ 60 ], geniposide [ 31 ], ginsenoside Rg5 [ 74 ], cryptotanshinone [ 29 ], isofraxidin [ 33 ], paeonol [ 56 ], crocin [ 43 ], coptisine [ 44 ], piperine [ 45 ], butein [ 46 ], licochalcone A [ 36 ], tectorigenin [ 48 ], theaflavin-3,3′-digallate [ 59 ], anemonin [ 49 ], gastrodin [ 51 ], compound K [ 37 ], and emodin [ 38 , 39 ] inhibit the expression of MMPs through a variety of pathways, such as IL-1β signaling, NF-κB signaling, AMPK signaling, MAPK signaling, and NO signaling, etc. The inhibition of cartilage catabolic processes by resveratrol [ 24 ], curcumin [ 66 ], and astragaloside IV [ 73 ] may be also related to their regulation on autophagy, activation of which may reduce the severity of OA.…”