Isoimperatorin ameliorates osteoarthritis by downregulating the mammalian target of rapamycin C1 signaling pathway

Abstract

Osteoarthritis (OA) is the most common disease of the joints, and is characterized by the breakdown of cartilage and degradation of the extracellular matrix. OA causes a high level of patient suffering and incurs large societal costs; however, the current strategies for treating OA are restricted due to limited understanding of the underlying molecular and cellular mechanisms. In the present study, the beneficial effects of isoimperatorin (Iso) were investigated using an experimental mouse model of OA, and its mechanism of action on primary chondrocytes was elucidated. Destabilization of the medial meniscus was performed on 8‑week‑old male mice to induce OA in the knees. Iso (500 mg/g/day) was intragastrically administered for 4 weeks. Degeneration of articular cartilage was assessed by histology using the Osteoarthritis Research Society International scoring system. The expression of matrix metalloproteinase (MMP)13, Runt‑related transcription factor (Runx)2, type X collagen (Col X) and vascular endothelial growth factor (VEGF) in the knee joints was examined by immunohistochemistry. In vitro, murine primary chondrocytes were treated with various concentrations of Iso, followed by 10 ng/ml interleukin‑1. The mRNA expression levels of MMP13, Runx2, Col X and VEGF were determined by reverse transcription‑quantitative polymerase chain reaction. The levels of autophagy and mammalian target of rapamycin (mTOR) signaling were determined by western blotting. Iso significantly ameliorated the severity of articular cartilage degradation in mice with experimental OA. The expression levels of MMP13, Runx2, Col X and VEGF were reduced in Iso‑treated mice. In murine primary chondrocytes, Iso also reduced MMP13, Runx2, Col X and VEGF expression, and activated autophagy by downregulating the mTOR complex 1 (mTORC1) signaling pathway. Therefore, the results of the present study demonstrated that Iso ameliorates OA‑induced pathological alterations by delaying chondrocyte deterioration, activating autophagy and inhibiting mTORC1, which suggests that Iso may have therapeutic potential for attenuating articular cartilage degradation and treating OA.

The Role of Autophagy in Osteoarthritis

“…Local application of rapamycin by intra-articular injection may be a potential therapy for OA (Takayama et al, 2014). Other drugs such as isoimperatorin and glucosamine can also activate autophagy and improve cell homeostasis by inhibiting mTOR pathway (Ouyang et al, 2017) (Figure 1). In addition, isoimperatorin improve the pathological changes induced by OA by reducing the expression of matrix metallopeptidase 13 (MMP13), RUNX family transcription factor 2 (RUNX2), collagen type X alpha 1 chain (COL10A1) and vascular endothelial growth factor A (VEGFA).…”

Isoimperatorin reduces the effective dose of dexamethasone in a murine model of asthma by inhibiting mast cell activation

“…ISO exerts inhibitory activity on the NO pathway, which may further contribute to its anti‐asthmatic activity (Huang et al, 2012; Matsuda et al, 2005). A large‐dose and long‐term administration of ISO may ameliorate osteoarthritis without any adverse effects (Ouyang, Jiang, Fang, Cui, & Cai, 2017; Tong, Xin, & Chen, 2017). In addition, we demonstrated that ISO restrained the activation of P38 MAPK in MCs, which is consistent with the result that ISO significantly decreases the phosphorylation of P38 MAPK in the lungs of asthmatic mice and LPS‐induced RAW 264.7 macrophages (Guo et al, 2012; Wijerathne et al, 2017), whereas the phosphorylation of ERK and P38 MAPK in activated MCs is not influenced by DEX (Koranteng et al, 2004).…”

New insights into the interplay between autophagy and cartilage degeneration in osteoarthritis

“…Many small molecule compounds and natural plant components play protective roles in OA by activating autophagy, such as isoimperatorin, delphinidin, celastrol, curcumin and astragaloside IV ( Liu, Meng, Jing, & Zhou, 2017 ; Ouyang, Jiang, Fang, Cui, & Cai, 2017 ; Lee et al, 2020 ; Xiao et al, 2020 ; Dai et al, 2021 ). Baicalin protects chondrocytes against the degradation of ECM through activating autophagy via miR-766-3p/AIFM1 axis ( Li, Cheng, & Liu, 2020 ).…”