Curcumin-Alleviated Osteoarthritic Progression in Rats Fed a High-Fat Diet by Inhibiting Apoptosis and Activating Autophagy via Modulation of MicroRNA-34a

Abstract

Purpose The mechanism underlying curcumin’s protective effect on osteoarthritis (OA) has not been clarified. This study aimed to determine whether curcumin exerts a chondroprotective effect by inhibiting apoptosis via upregulation of E2F1/PITX1 and activation of autophagy via the Akt/mTOR pathway by targeting microRNA-34a (miR-34a). Methods Male Sprague–Dawley rats were fed a normal diet (ND) or high-fat diet (HFD) for 28 weeks. Five rats from each diet group were selected randomly for histological analysis of OA characteristics. Rats fed a HFD were given a single intra-stifle joint injection of the miR-34a mimic agomir-34a or negative control agomir (NC), followed by weekly low-dose (200 μg/kg body weight) or high-dose (400 μg/kg body weight) curcumin intra-joint injections from weeks 29 to 32. The rats’ stifle joints were submitted to histological analysis and to an apoptotic assay. Expression of miR-34a was detected using a real-time RT-PCR. E2F1 and PITX1 protein levels were determined by Western blot analysis, and the expressions of Beclin1, LC3B, p62, phosphorylated (p)-Akt, and p-mTOR were measured using immunofluorescence analysis. Results We found that rats fed a HFD had OA-like lesions in their articular cartilage and had increased apoptosis of chondrocytes and decreased autophagy compared to rats fed a ND. Curcumin treatment alleviated OA changes, inhibited apoptosis, and upregulated autophagy. Agomir-34a treatment reduced E2F1, PITX1, Beclin1, and LC3B expression and increased p62, p-Akt, and p-mTOR expression in HFD-fed rats given low- or high-dose curcumin. Greater numbers of apoptotic cells, lesser expression of p62, p-Akt, and p-mTOR, and greater expression of E2F1, PITX1, and LC3B were observed in the agomir-34a and high-dose curcumin-treated group than in agomir-34a and low-dose curcumin-treated group. Conclusion Curcumin’s chondroprotective effect was mediated by its suppression of miR-34a, apparently by reducing apoptosis, via upregulation of E2F1/PITX1, and by augmenting autophagy, likely via the Akt/mTOR pathway.

Effect of Dietary Polyphenols on Osteoarthritis—Molecular Mechanisms

“…Curcumin is the most researched type of curcuminoid due to its potent antioxidant, anti-inflammatory, antimicrobial, antirheumatic, neuroprotective, anticancer, hepatoprotective, and cardioprotective properties [ 68 ]. Several studies have reported the pain-alleviating properties and the chondroprotective effects of curcumin and curcuminoids in clinical, in vivo, and in vitro studies [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ] ( Table 1 ).…”

“…Numerous in vivo models have validated the analgesic effects of curcuminoids and, in addition, provided mechanistic insights into their chondroprotective effects in an OA-induced rat model [ 61 , 62 , 63 ]. For example, curcumin supplementation in rats fed with a high-fat diet for 28 weeks inhibited apoptosis via increasing the expression of E2F1/PITX1; it also upregulated autophagy through the Akt/mTOR pathway by reducing the microRNA-34a [ 61 ]. In another recent study, a highly bioavailable formulation of curcumin (64.7 times more bioavailable) was tested for its protective effects against monosodium iodoacetate (MIA)-induced knee OA in rats [ 62 ].…”

“…Ameliorated the pathophysiology ↓ joint degradation and exhibited chondroprotective effect in OA-induced rat model [ 61 , 62 , 63 , 64 ]…”

Phytochemicals Mediate Autophagy Against Osteoarthritis by Maintaining Cartilage Homeostasis

“…By establishing aging spontaneous OA and the destabilization of the medial meniscus (DMM) surgery-induced OA models in mice, Zhang et al found that curcumin treatment promoted autophagy by suppressing the protein kinase B/mechanistic target of rapamycin kinase (AKT/mTOR) signaling pathway enhanced autophagy and reduced apoptosis and cartilage loss ( Zhang et al, 2018a) . Yao et al established a rat model of OA by feeding a high-fat diet and injected curcumin into the knee joints of OA rats and found that the chondroprotective effect of curcumin may be achieved in part through inhibition of AKT/mTOR pathway autophagy ( Yao et al, 2021 ). Besides, there is a study confirming that curcumin has been used clinically and has been shown to improve pain in patients with mild to moderate OA.…”

Nucleoporin 160 (NUP160) inhibition alleviates diabetic nephropathy by activating autophagy

“…Immunofluorescence staining was used to detect the light chain 3 (LC3) level [ 30 ]. The tissue sections were incubated with the primary antibody LC3B (ab192890, 1:200, Abcam) for 12 h at 4°C, and subsequently incubated with Fluorescent-conjugated goat anti-rabbit IgG for 2 h at 37°C.…”