Ginsenoside Rb1 inhibits matrix metalloproteinase 13 through down-regulating Notch signaling pathway in osteoarthritis

Abstract

Mounting evidence suggests that an excess of matrix metalloproteinase-13 (MMP-13) plays an important role in the breakdown of extracellular matrix in osteoarthritis (OA). Here, the effects of ginsenoside Rb1 (GRb1) on the expression of MMP-13 in IL-1β-induced SW 1353 chondrosarcoma cells and an experimental rat model of OA induced by anterior cruciate ligament transection (ACLT) were investigated. SW1353 chondrosarcoma cells were pretreated with or without GRb1 and Notch signaling pathway inhibitor, DAPT, then were stimulated with IL-1β. In rats, experimental OA was induced by ACLT. These rats then received intra-articular injections of vehicle, an inhibitor of γ-secretase, DAPT, and/or GRb1. Expression of MMP-13, collagen type II (CII), Notch1, and jagged 1 (JAG1) were verified by western blotting and immunohistochemistry. In addition, levels of MMP-13 mRNA were detected using quantitative real-time PCR. In histological analyses, treatment with DAPT reduced the number of cartilage lesions present and the expressions of MMP-13, CII, Notch1, and JAG1. In addition, treatment with GRb1 was associated with lower levels of Notch1 and JAG1 in both IL-1β-induced SW1353 chondrosarcoma cells and in the rat OA model. Furthermore, the suppressive effect of GRb1 on MMP-13 was greater than that exhibited by the signaling pathway inhibitor. In conclusion, GRb1 inhibits MMP-13 through down-regulating Notch signaling pathway in OA.

Insights into the Action Mechanisms of Traditional Chinese Medicine in Osteoarthritis

“…Whereas it downregulates the ECM catabolic factors MMP-1 and MMP-13 [ 40 , 41 ]. Additionally, MMP-13 is positively associated with Notch signaling, which can be suppressed by Rb1 [ 82 ]. Pinocembrin, a flavonoid extracted from propolis, inhibits the nuclear translocation of p65 and phosphorylation and degradation of I κ B α induced by TNF α in human chondrocytes, leading to suppression of MMP-3 and MMP-13 expression [ 83 ].…”

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

“…Catabolic reactions take place in the OA cartilage, in which collagen and aggrecan are degraded [63]. MMPs are a family of zinc containing, calcium-dependent neutral proteases which can initiate the cleavage of type II collagen and aggrecan [76]. 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].…”

“…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…”

“…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.…”

Activation of NOTCH1 by Shear Force Elicits Immediate Cytokine Expression in Human Chondrocytes

“…Evidences have also shown that NOTCH1 is frequently activated in the chondrocytes of OA cartilage [ 22 , 23 , 24 , 25 ]. Inhibition of NOTCH1 activation by γ-secretase inhibitor restores the decreased expression of collagen II and suppresses MMP13 expression [ 26 ]. Hence, activation of NOTCH1 signaling likely plays an important role in the pathogenesis of OA.…”