NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis
Silicosis is a disease caused by prolonged exposure to silica dust. It is the most typical, rapidly progressive, and fatal form of pneumoconiosis. Currently, there is no specific medication available for the treatment of silicosis. LOXL2 is a copper-dependent lysine oxidase whose main function is to...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324016488 |
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| author | Lan Peng Wenqing Sun Demin Cheng Xinying Jia Wenxiu Lian Ziwei Li Haojie Xiong Ting Wang Yi Liu Chunhui Ni |
| author_facet | Lan Peng Wenqing Sun Demin Cheng Xinying Jia Wenxiu Lian Ziwei Li Haojie Xiong Ting Wang Yi Liu Chunhui Ni |
| author_sort | Lan Peng |
| collection | DOAJ |
| description | Silicosis is a disease caused by prolonged exposure to silica dust. It is the most typical, rapidly progressive, and fatal form of pneumoconiosis. Currently, there is no specific medication available for the treatment of silicosis. LOXL2 is a copper-dependent lysine oxidase whose main function is to catalyze the cross-linking of extracellular matrix components, particularly collagen and elastin. However, few researchers have investigated the role of LOXL2 in the pathogenesis of silicosis. In this study, we demonstrated that LOXL2 is upregulated in silica-inhaled mouse lung tissue and in a TGF-β-induced fibroblast model. In vitro, we confirmed that LOXL2 functions to promote ECM deposition by binding directly to collagen and elastin. We then used scavenger receptor cysteine-rich (SRCR) domains to show that LOXL2 can induce fibrosis independently of its enzymatic activity. Furthermore, we discovered that NUDT21, the LOXL2 upstream regulatory mechanism of LOXL2, alters LOXL2's 3′UTR usage by substituting alternative polyadenylation (APA), thereby modulating LOXL2 expression. By injecting LOXL2 siRNA-loaded liposomes into the tail vein of mice in the silica dust-treated mouse pulmonary fibrosis model, the severity of lung fibrosis was significantly reduced. In this context, LOXL2 is regulated by NUDT21 and may affect pulmonary fibrosis by influencing the cross-linking of ECM proteins. Our research provides a scientific basis for the development of new anti-fibrosis treatment strategies. |
| format | Article |
| id | doaj-art-0abc680cfbfe4d019823798ab05ba3f2 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-0abc680cfbfe4d019823798ab05ba3f22025-02-12T05:29:51ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01290117572NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosisLan Peng0Wenqing Sun1Demin Cheng2Xinying Jia3Wenxiu Lian4Ziwei Li5Haojie Xiong6Ting Wang7Yi Liu8Chunhui Ni9Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaThe Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing medical university, Wuxi, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210003, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Correspondence to: 499 818 Tianyuan East Road, Nanjing 211166, China.Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of Public Health, Kangda College of Nanjing Medical University, Lianyungang, 320700, China; Correspondence to: 818 Tianyuan East Road, Nanjing 211166, China.Silicosis is a disease caused by prolonged exposure to silica dust. It is the most typical, rapidly progressive, and fatal form of pneumoconiosis. Currently, there is no specific medication available for the treatment of silicosis. LOXL2 is a copper-dependent lysine oxidase whose main function is to catalyze the cross-linking of extracellular matrix components, particularly collagen and elastin. However, few researchers have investigated the role of LOXL2 in the pathogenesis of silicosis. In this study, we demonstrated that LOXL2 is upregulated in silica-inhaled mouse lung tissue and in a TGF-β-induced fibroblast model. In vitro, we confirmed that LOXL2 functions to promote ECM deposition by binding directly to collagen and elastin. We then used scavenger receptor cysteine-rich (SRCR) domains to show that LOXL2 can induce fibrosis independently of its enzymatic activity. Furthermore, we discovered that NUDT21, the LOXL2 upstream regulatory mechanism of LOXL2, alters LOXL2's 3′UTR usage by substituting alternative polyadenylation (APA), thereby modulating LOXL2 expression. By injecting LOXL2 siRNA-loaded liposomes into the tail vein of mice in the silica dust-treated mouse pulmonary fibrosis model, the severity of lung fibrosis was significantly reduced. In this context, LOXL2 is regulated by NUDT21 and may affect pulmonary fibrosis by influencing the cross-linking of ECM proteins. Our research provides a scientific basis for the development of new anti-fibrosis treatment strategies.http://www.sciencedirect.com/science/article/pii/S0147651324016488SilicosisLOXL2NUDT21ECM cross-linkLiposomal treatment |
| spellingShingle | Lan Peng Wenqing Sun Demin Cheng Xinying Jia Wenxiu Lian Ziwei Li Haojie Xiong Ting Wang Yi Liu Chunhui Ni NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis Ecotoxicology and Environmental Safety Silicosis LOXL2 NUDT21 ECM cross-link Liposomal treatment |
| title | NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis |
| title_full | NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis |
| title_fullStr | NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis |
| title_full_unstemmed | NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis |
| title_short | NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis |
| title_sort | nudt21 regulates lysyl oxidase like 2 loxl2 to influence ecm protein cross linking in silica induced pulmonary fibrosis |
| topic | Silicosis LOXL2 NUDT21 ECM cross-link Liposomal treatment |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324016488 |
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