ArticleParticle and fibre toxicology2023
MMP-3-mediated cleavage of OPN is involved in copper oxide nanoparticle-induced activation of fibroblasts.
Article in Particle and fibre toxicology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 26 citations in OpenAlex.
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- Clinical significance of secreted phosphoprotein-1 overexpression in cancers.International journal of clinical oncology · 2026Article
- Integrated Multi-Endpoint Analysis of Soluble Copper(II) Chloride-Induced Oxidative Stress, Mitochondrial Dysfunction, and Genotoxicity in RAW264.7 Macrophages.Biological trace element research · 2026Article
- Multimodal feature fusion machine learning for predicting chronic injury induced by engineered nanomaterials.Nature communications · 2025Article
- The Journey of Copper-Impregnated Dressings in Wound Healing: From a Medical Hypothesis to Clinical Practice.Biomedicines · 2025Review
- The Trilogy of Skin Regeneration via Metal-Organic Frameworks Nanomedicine: Precision Management of Refractory Wounds, Pathological Scarring, and Hair Follicle Reactivation.International journal of nanomedicine · 2025Review
- The immune duality of osteopontin and its therapeutic implications for kidney transplantation.Frontiers in immunology · 2025Review
- HMGB1 derived from lung epithelial cells after cobalt nanoparticle exposure promotes the activation of lung fibroblasts.Nanotoxicology · 2024Article
- MMP-3 mediates copper oxide nanoparticle-induced pulmonary inflammation and fibrosis.Journal of nanobiotechnology · 2024Article
- RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin-RGD interactions.Cancer medicine · 2024Review
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Authors and funding
5 authors at 2 institutions in 1 country.
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Abstract
backgroundCopper oxide nanoparticles (Nano-CuO) are one of the most produced and used nanomaterials. Previous studies have shown that exposure to Nano-CuO caused acute lung injury, inflammation, and fibrosis. However, the mechanisms underlying Nano-CuO-induced lung fibrosis are still unclear. Here, we hypothesized that exposure of human lung epithelial cells and macrophages to Nano-CuO would upregulate MMP-3, which cleaved osteopontin (OPN), resulting in fibroblast activation and lung fibrosis.
methodsA triple co-culture model was established to explore the mechanisms underlying Nano-CuO-induced fibroblast activation. Cytotoxicity of Nano-CuO on BEAS-2B, U937* macrophages, and MRC-5 fibroblasts were determined by alamarBlue and MTS assays. The expression or activity of MMP-3, OPN, and fibrosis-associated proteins was determined by Western blot or zymography assay. Migration of MRC-5 fibroblasts was evaluated by wound healing assay. MMP-3 siRNA and an RGD-containing peptide, GRGDSP, were used to explore the role of MMP-3 and cleaved OPN in fibroblast activation.
resultsExposure to non-cytotoxic doses of Nano-CuO (0.5 and 1 µg/mL) caused increased expression and activity of MMP-3 in the conditioned media of BEAS-2B and U937* cells, but not MRC-5 fibroblasts. Nano-CuO exposure also caused increased production of cleaved OPN fragments, which was abolished by MMP-3 siRNA transfection. Conditioned media from Nano-CuO-exposed BEAS-2B, U937*, or the co-culture of BEAS-2B and U937* caused activation of unexposed MRC-5 fibroblasts. However, direct exposure of MRC-5 fibroblasts to Nano-CuO did not induce their activation. In a triple co-culture system, exposure of BEAS-2B and U937* cells to Nano-CuO caused activation of unexposed MRC-5 fibroblasts, while transfection of MMP-3 siRNA in BEAS-2B and U937* cells significantly inhibited the activation and migration of MRC-5 fibroblasts. In addition, pretreatment with GRGDSP peptide inhibited Nano-CuO-induced activation and migration of MRC-5 fibroblasts in the triple co-culture system.
conclusionsOur results demonstrated that Nano-CuO exposure caused increased production of MMP-3 from lung epithelial BEAS-2B cells and U937* macrophages, which cleaved OPN, resulting in the activation of lung fibroblasts MRC-5. These results suggest that MMP-3-cleaved OPN may play a key role in Nano-CuO-induced activation of lung fibroblasts. More investigations are needed to confirm whether these effects are due to the nanoparticles themselves and/or Cu ions.
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