Betulin Alleviates the Inflammatory Response in Mouse Chondrocytes and Ameliorates Osteoarthritis via AKT/Nrf2/HO-1/NF-κB Axis

Abstract

Osteoarthritis (OA) is a common degenerative joint disease featuring the degeneration, destruction, and ossification of cartilage. Inflammation which may facilitate OA occurrence and development is considered as the main pathological factor. Betulin, a natural product extracted from birch bark, has been commonly used for inflammation treatment; however, its role in OA remains unclear. This study is aimed to explore whether betulin can suppress IL-1β–induced inflammation in chondrocytes and alleviate OA in vitro and in vivo. In in vitro studies, the generation of pro-inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), and nitric oxide (NO), was assessed using the enzyme-linked immunosorbent assay (ELISA) and Griess reaction. As revealed by results, betulin inhibited the expression of pro-inflammatory mediators. In addition, the protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP-13), thrombospondin motifs 5 (ADAMTS5), Collagen II, and Aggrecan were quantified using Western blot analysis. We found that betulin could inhibit the generation of COX-2 and iNOS induced by IL-1β, indicating that betulin has anti-inflammatory effects in chondrocytes. Furthermore, betulin downregulates the expression of MMP-13 and ADAMTS-5 and upregulates the expression of Collagen II and Aggrecan, indicating that it can inhibit the degradation of the extracellular matrix. In mechanism, betulin activated the AKT/Nrf2 pathway and inhibited the phosphorylation of p65. In in vivo studies, administration of betulin in vivo could inhibit cartilage destruction and inflammatory progression. Therefore, these findings suggest that betulin may alleviate IL-1β–induced OA via the AKT/Nrf2/HO-1/NF-κB signal axis, and betulin may be a potential drug for the treatment of OA.

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

“…Although research and development of small molecule inhibitors of SREBP-1 is necessary, the number of existing inhibitors (such as fatostatin, FGH10019, betulin, and PF-429242) is small and the reports are few, and they have not entered clinical application ( Kamisuki et al, 2011 ; Zou et al, 2021b ; Wang T. B. et al, 2021 ; Ren et al, 2021 ). In addition to these, a recent report by Zou et al (2021) found a relationship between the expression level of SREBP-1 in HCC tissues and the prognosis of HCC RFA, and used a novel small molecule inhibitor of SREBP-1 in combination with RFA to achieve a better anti-tumor effect on HCC ( Trott and Olson, 2010 ).…”

The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis

“…Additionally, TNF-α and IL-1β induce COMP degradation. IL-1β also activates nuclear transcription factors to further stimulate the secretion of pro-inflammatory mediators [ 184 ].…”

Ononin ameliorates inflammation and cartilage degradation in rat chondrocytes with IL-1β-induced osteoarthritis by downregulating the MAPK and NF-κB pathways

“…Previous studies have shown that a growing number of Chinese herbal compounds also have anti-inflammatory effects against OA, which was consistent with our results. For instance, betulin can inhibit the degradation of extracellular matrix by downregulating the expression of MMP-13 and upregulating the expression of collagen II [ 37 ]. Another agent, xanthohumol, a natural prenylflavonoid with anti-inflammatory and antioxidant activities, has also been shown to effectively protect against ECM degradation by ameliorating MMP-13 expression in OA chondrocytes [ 38 ].…”