A glucuronated flavone TMMG spatially targets chondrocytes to alleviate cartilage degeneration through negative regulation of IL-1β

• Published in: Biomedicine & pharmacotherapy Vol. 163; p. 114809
• Main Authors: Kothari, Priyanka, Dhaniya, Geeta, Sardar, Anirban, Sinha, Shradha, Girme, Aboli, Rai, Divya, Chutani, Kunal, Hingorani, Lal, Trivedi, Ritu
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.07.2023; Elsevier
• Subjects: ACLT; Animals; Cartilage, Articular - metabolism; Cells, Cultured; Chondrocytes - metabolism; Flavones - pharmacology; Flavones - therapeutic use; IL-1β; Interleukin-1beta - metabolism; Macrophage; Mice; Osteoarthritis; Osteoarthritis - metabolism; Osteoclast; Prospective Studies; TMMG; MMPs; Osteoclast; IL-1β; LPS; COMP; OA; TMMG; ACLT; ROS; CTX-II; Osteoarthritis; PCR; Macrophage
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114809

Chondrocytes are the only resident cell types that form the extracellular matrix of cartilage. Inflammation alters the anabolic and catabolic regulation of chondrocytes, resulting in the progression of osteoarthritis (OA). The potential of TMMG, a glucuronated flavone, was explored against the pathophysiology of OA in both in vitro and in vivo models. The effects of TMMG were evaluated on chondrocytes and the ATDC5 cell line treated with IL-1β in an established in vitro inflammatory OA model. An anterior cruciate ligament transection (ACLT) model was used to simulate post-traumatic injury in vivo. Micro-CT and histological examination were employed to examine the micro-architectural status and cartilage alteration. Further, serum biomarkers were measured using ELISA to assess OA progression. In-vitro, TMMG reduced excessive ROS generation and inhibited pro-inflammatory IL-1β secretion by mouse chondrocytes and macrophages, which contributes to OA progression. This expression pattern closely mirrored osteoclastogenesis prevention. In-vivo results show that TMMG prevented chondrocyte apoptosis and degradation of articular cartilage thickness, subchondral parameters, and elevated serum COMP, CTX-II, and IL-1β which were significantly restored in 5 and 10 mg.kg−1day−1 treated animals and comparable to the positive control Indomethacin. In addition, TMMG also improved cartilage integrity and decreased the OARSI score by maintaining chondrocyte numbers and delaying ECM degradation. These findings suggest that TMMG may be a prospective disease-modifying agent that can mitigate OA progression. [Display omitted] •TMMG inhibited excessive ROS generation & cytokine secretion in IL-1β induced cells.•TMMG inhibited chondrocyte apoptosis and matrix degradation in ACLT animals.•TMMG improved radiological appearance and subchondral bone microarchitecture in OA.•Elevated subchondral bone resorption and serum biomarkers were regulated by TMMG.