3,3'-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

Hao Tang; Kunpeng Qin; Anquan Wang; Shuang Li; Sheng Fang; Weilu Gao; Ming Lu; Wei Huang; Hui Zhang; Zongsheng Yin

doi:10.3389/fphar.2022.999851

3,3'-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

Front Pharmacol. 2022 Nov 10:13:999851. doi: 10.3389/fphar.2022.999851. eCollection 2022.

Authors

Hao Tang^{1

2}, Kunpeng Qin¹, Anquan Wang¹, Shuang Li¹, Sheng Fang³, Weilu Gao¹, Ming Lu¹, Wei Huang⁴, Hui Zhang¹, Zongsheng Yin¹

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
² The Key Laboratory of Microbiology and Parasitology of Anhui Province, The Key Laboratory of Zoonoses of High Institutions in Anhui, Anhui Medical University, Hefei, China.
³ Department of Orthopedics, The Second People's Hospital of Hefei, Hefei, China.
⁴ Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by articular cartilage destruction. The pathological mechanisms are complex; in particular, inflammation, autophagy, and apoptosis are often involved. 3,3-Diindolylmethane (DIM), a phytoconstituent extracted from cruciferous vegetables, has various effects such as anti-inflammatory, antioxidant and anti-apoptotic. However, the effects of DIM on osteoarthritic chondrocytes remain undetermined. In this study, we simulated a lipopolysaccharide (LPS)-induced osteoarthritis model in human primary chondrocytes. We found that LPS stimulation significantly inhibited autophagy, induced chondrocyte apoptosis and extracellular matrix (ECM) degradation, which could be ameliorated by DIM. DIM inhibited the expression of a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), matrix metalloproteinase 13 (MMP13), cleaved caspase-3, Bax, and p62, and increased the expression level of collagen II, aggrecan, Bcl-2, light chain 3 Ⅱ (LC3 Ⅱ), and beclin-1. Mechanistic studies showed that DIM increased chondrocyte autophagy levels by inhibiting the activation of PI3K/AKT/mTOR pathway. In mice destabilization of the medial meniscus (DMM) model, immunohistochemical analysis showed that DIM inhibited the expression of p-PI3K and cleaved caspase-3, increased the expression of LC3 Ⅱ. Furthermore, DIM relieved joint cartilage degeneration. In conclusion, our findings demonstrate for the first time that DIM inhibits LPS-induced chondrocyte apoptosis and ECM degradation by regulating the PI3K/AKT/mTOR-autophagy axis and delays OA progression in vivo.

Keywords: 3, 3′-diindolylmethane; apoptosis; autophagy; chondrocyte; osteoarthritis.