Tabersonine-mediated inhibition of the PI3K/AKT signaling pathway modulates macrophage reprogramming and alleviates osteoarthritis.

Abstract

Osteoarthritis (OA) is a common degenerative joint disease primarily marked by cartilage breakdown, with synovitis driving disease progression. During disease exacerbation, macrophages in synovial tissue predominantly polarize to the M1 phenotype. Tabersonine (TAB), derived from Catharanthus roseus, exhibits anti-inflammatory properties, yet its exact mechanism in osteoarthritis remains elusive. In vitro and in vivo experiments were performed to evaluate the effects of TAB on macrophage inflammatory responses and OA-related cartilage changes. The experimental design included LPS stimulation of RAW264.7 cells for quantitative analysis of inflammatory mediator production. TAB's effect on macrophage polarization was assessed by immunofluorescence, Western blot, and flow cytometry. Treated cells were cultured together with ATDC5 chondrocytes to assess extracellular matrix synthesis and degradation-related molecule expression. In vivo, osteoarthritis was induced in rat knees via anterior cruciate ligament transection (ACLT) to assess TAB's role in joint degeneration. In vitro experiments showed that TAB effectively inhibited LPS-induced macrophage inflammation and promoted macrophage reprogramming toward an M2-like phenotype. Transcriptome analysis demonstrated that TAB inhibited the PI3K/AKT signaling pathway in macrophages stimulated by LPS. Cell studies demonstrated that TAB regulated M1/M2 polarization via PI3K/AKT inhibition and enhanced the production of cartilage regeneration-related molecules. In vivo, TAB attenuated cartilage degeneration in ACLT rats. TAB protects cartilage by modulating macrophage reprogramming and inhibiting chondrocyte extracellular matrix degradation through the PI3K/AKT signaling pathway.

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