PI3K/Akt inhibition mediates benzophenone-3-induced chondrocyte apoptosis in pollutant-driven osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease. Benzophenone-3 (BP-3), a commonly used ultraviolet filter in personal care products, has been positively correlated with an increased risk of OA. However, direct in vivo evidence linking BP-3 exposure to cartilage pathology is limited. Here, we show that 24-week BP-3 exposure in mice leads to a dose-dependent accumulation of BP-3 and its metabolite BP-8 in knee joint tissues, which is a previously unrecognized finding. Histological analysis revealed that BP-3 exposure induced OA-like structural alterations in mouse knee joints, including chondrocyte disorganization, surface fibrosis, and even superficial layer disruption of cartilage. Both in vivo and in vitro experiments demonstrate that BP-3 exposure disrupts the homeostasis of the extracellular matrix (ECM) evidenced by upregulation of matrix metalloproteinase-13 (MMP13) and decrease of type II collagen (Col2a1), as well as increases apoptosis markers including BCL2 associated x protein (Bax) and Cleaved caspase-3. Transcriptome analysis identified the Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) signaling pathway as a key regulator of apoptosis. In vitro, BP-3 exposure reduces phosphorylation of PI3K and Akt, whereas activation of this pathway with insulin-like growth factor 1 (IGF-1) ameliorates BP-3-induced apoptosis and ECM degradation. Collectively, this study first demonstrates in vivo bioaccumulation of BP-3 in joint tissues, and shows that PI3K/Akt inhibition mediates BP-3-induced chondrocyte apoptosis, establishing a mechanistic link to OA.