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.
Highlights
Osteoarthritis (OA) is one of the most common degenerative joint disorders in elderly people
Western Blot experiments confirmed that KGN down-regulated the protein levels of matrix degradation enzymes (MMP13 and a disintegrin metalloproteinase with thrombospondin motifs 5 (ADAMTS5)), whereas it barely altered the expression of matrix synthesis proteins (COL II and Aggrecan) in normal chondrocytes (Fig. 1E, F)
The Tb.Th ratio of destabilization of medial meniscus (DMM) group was significantly higher than that of Sham group, which was not affected by KGN treatment (Fig. 4D). These findings suggest that KGN, at high concentrations, protected articular cartilage from DMM-induced matrix degradation and ameliorated the pathological sclerosis of subchondral bone
Summary
Osteoarthritis (OA) is one of the most common degenerative joint disorders in elderly people. Hou et al Cell Death and Disease (2021)12:483 damage of articular cartilage[3]. This underlines the urgent needed to develop new and effective interventions against cartilage degeneration. Kartogenin (KGN) is a small bioactive molecule that was first reported to promote chondrogenic differentiation of bone marrow mesenchymal stem cells (MSCs)[4]. KGN improves the development of cartilage nodule and synovial joint through the transforming growth factor β (TGFβ) signaling pathway[5]. We found KGN repressed production of reactive oxygen species (ROS) and improved cellular antioxidant functions in human bone marrow MSCs by upregulating the expression of silent information regulator type 1 (SIRT1)[8], suggesting that KGN may ameliorate OAinduced cartilage degradation by attenuating oxidative stress
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
