Kartogenin prevents cartilage degradation and alleviates osteoarthritis progression in mice via the miR-146a/NRF2 axis

Abstract

Osteoarthritis (OA) is a common articular degenerative disease characterized by loss of cartilage matrix and subchondral bone sclerosis. Kartogenin (KGN) has been reported to improve chondrogenic differentiation of mesenchymal stem cells. However, the therapeutic effect of KGN on OA-induced cartilage degeneration was still unclear. This study aimed to explore the protective effects and underlying mechanisms of KGN on articular cartilage degradation using mice with post-traumatic OA. To mimic the in vivo arthritic environment, in vitro cultured chondrocytes were exposed to interleukin-1β (IL-1β). We found that KGN barely affected the cell proliferation of chondrocytes; however, KGN significantly enhanced the synthesis of cartilage matrix components such as type II collagen and aggrecan in a dose-dependent manner. Meanwhile, KGN markedly suppressed the expression of matrix degradation enzymes such as MMP13 and ADAMTS5. In vivo experiments showed that intra-articular administration of KGN ameliorated cartilage degeneration and inhibited subchondral bone sclerosis in an experimental OA mouse model. Molecular biology experiments revealed that KGN modulated intracellular reactive oxygen species in IL-1β-stimulated chondrocytes by up-regulating nuclear factor erythroid 2-related factor 2 (NRF2), while barely affecting its mRNA expression. Microarray analysis further revealed that IL-1β significantly up-regulated miR-146a that played a critical role in regulating the protein levels of NRF2. KGN treatment showed a strong inhibitory effect on the expression of miR-146a in IL-1β-stimulated chondrocytes. Over-expression of miR-146a abolished the anti-arthritic effects of KGN not only by down-regulating the protein levels of NRF2 but also by up-regulating the expression of matrix degradation enzymes. Our findings demonstrate, for the first time, that KGN exerts anti-arthritic effects via activation of the miR-146a-NRF2 axis and KGN is a promising heterocyclic molecule to prevent OA-induced cartilage degeneration.

Selective STAT3 Inhibitor Alantolactone Ameliorates Osteoarthritis via Regulating Chondrocyte Autophagy and Cartilage Homeostasis

“…IL-1β could significantly restrain the synthesis of collagen II and enhanced of inflammatory factors, such as iNOS and COX2. Previous studies reported that the stimulation of IL-1β (10 ng/ml) for 24 h could induce inflammation in chondrocytes ( Huang et al, 2019 ; Hou et al, 2021 ). In this study, IL-1β (10 ng/ml) induced inflammatory responses in mouse chondrocytes indeed.…”

Repair of osteochondral defects mediated by double-layer scaffolds with natural osteochondral-biomimetic microenvironment and interface

“…KEGG pathway analysis and GO functional enrichment of up-regulated DEGs results ( Fig. 6 C1, D1, Table S2A ) found that several cartilage-related pathways and bioprocesses, as well as cartilage-specific genes (COL II, ACAN, and SOX9), were significantly activated, such as the MAPK signaling pathway [ [51] , [52] , [53] ], cartilage development, glycosaminoglycan biosynthetic process, and negative regulation of smooth muscle cell proliferation. These signaling pathways, bioprocesses, and specific genes were related to the positive regulation of the chondrogenic differentiation, cartilage development, ECM synthesis, and negative regulation of angiogenesis, implying that ACM powder promoted chondrogenic differentiation and cartilage regeneration of BMSCs and inhibited the development of blood vessel, which benefited enhancing the stability of BMSC-regenerated cartilage.…”

Arbutin-Modified Microspheres Prevent Osteoarthritis Progression by Mobilizing Local Anti-Inflammatory and Antioxidant Responses

“…Strengthening the Nrf2-HO-1 pathway not only alleviates OA-related oxidative stress injury but also bene ts ECM anabolic metabolism to protect against OA. A possible upstream mediator of Nrf2 was revealed to be microRNA (miRNA)-146a-5p, which targets the 3' untranslated region (3'UTR) of Nrf2 to block its translational process [27]. Indeed, the other miRNAs are considered potential regulators of Nrf2, such as miR-132 [28], miR-27a [29], or miR-3175 [30], some of which may be targets of ARB but need further corroboration.…”