Frontiers in bioscience (Landmark edition) · 2026
METTL16 Modulates GPX4 Expression to Regulate Chondrocyte Ferroptosis.
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He Li, Tong Xing, Yang Ming, Wang Xiaoming, Wang Xiaowei, Wang Bing
Аннотация
BACKGROUND: Achondroplasia (ACH), the predominant inherited form of disproportionate short stature, results from specific genetic alterations in fibroblast growth factor receptor 3 (FGFR3). N6-methyladenosine (m6A) modification is reported to modulate mRNA stability and translation. The present investigation systematically explored the epigenetic regulatory function of METTL16, an m6A RNA methyltransferase, within the pathophysiological framework of ACH.
METHODS: We generated an ACH mouse model via Fgfr3380R (Fgfr3ach) gene mutation. Primary chondrocytes were isolated from newborn mice and stimulated with IL-1β to induce cell death. Proximal tibia tissues were collected and analyzed with HE staining, toluidine blue staining, safranin O staining, and immunohistochemical (IHC) analysis. Bone structure was analyzed by measuring bone mineral density (BMD), ratio of bone volume to total tissue volume (BV/TV), trabecular number (TbN), and trabecular thickness (TbTh). Cell viability and proliferation were assessed using the Cell Counting Kit-8 (CCK-8) and colony formation assays. The levels of iron (Fe2+), malondialdehyde (MDA), and glutathione (GSH) were measured to assess ferroptosis. Protein and RNA levels were measured by western blotting and quantitative real-time PCR (qPCR) assay, respectively, while the m6A modification level was assessed by m6A mRNA immunoprecipitation (IP).
RESULTS: METTL16 improved bone chondrogenesis in the ACH mouse model, with METTL16 overexpression promoting the proliferation of primary chondrocytes. METTL16 decreased ferroptosis both in vitro and in vivo and increased glutathione peroxidase 4 (GPX4) expression. METTL16 enhanced m6A modification of GPX4 mRNA and suppressed its degradation. Depletion of GPX4 abolished the effects of METTL16 on ACH mice and chondrocytes.
CONCLUSION: Overexpression of METTL16 improved bone growth and alleviated ferroptosis of chondrocytes by increasing m6A modification of GPX4 mRNA and thus GPX4 expression in chondrocytes. The METTL16/GPX4 axis may be a promising therapeutic approach for ACH treatment.
METHODS: We generated an ACH mouse model via Fgfr3380R (Fgfr3ach) gene mutation. Primary chondrocytes were isolated from newborn mice and stimulated with IL-1β to induce cell death. Proximal tibia tissues were collected and analyzed with HE staining, toluidine blue staining, safranin O staining, and immunohistochemical (IHC) analysis. Bone structure was analyzed by measuring bone mineral density (BMD), ratio of bone volume to total tissue volume (BV/TV), trabecular number (TbN), and trabecular thickness (TbTh). Cell viability and proliferation were assessed using the Cell Counting Kit-8 (CCK-8) and colony formation assays. The levels of iron (Fe2+), malondialdehyde (MDA), and glutathione (GSH) were measured to assess ferroptosis. Protein and RNA levels were measured by western blotting and quantitative real-time PCR (qPCR) assay, respectively, while the m6A modification level was assessed by m6A mRNA immunoprecipitation (IP).
RESULTS: METTL16 improved bone chondrogenesis in the ACH mouse model, with METTL16 overexpression promoting the proliferation of primary chondrocytes. METTL16 decreased ferroptosis both in vitro and in vivo and increased glutathione peroxidase 4 (GPX4) expression. METTL16 enhanced m6A modification of GPX4 mRNA and suppressed its degradation. Depletion of GPX4 abolished the effects of METTL16 on ACH mice and chondrocytes.
CONCLUSION: Overexpression of METTL16 improved bone growth and alleviated ferroptosis of chondrocytes by increasing m6A modification of GPX4 mRNA and thus GPX4 expression in chondrocytes. The METTL16/GPX4 axis may be a promising therapeutic approach for ACH treatment.