Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum
Pseudoxanthoma elasticum (PXE), caused by pathogenic variants in ABCC6, is characterized by pathological ectopic calcification with poorly understood mechanisms and no effective therapies. To address this, we developed the first zebrafish model of human PXE by introducing the pathogenic ABCC6 point...
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Elsevier
2025-09-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580825002912 |
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| author | Jianjian Sun Jichang Huang Renjie Zhang Shubin Zhang Tao P. Zhong Ping Zhu |
| author_facet | Jianjian Sun Jichang Huang Renjie Zhang Shubin Zhang Tao P. Zhong Ping Zhu |
| author_sort | Jianjian Sun |
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| description | Pseudoxanthoma elasticum (PXE), caused by pathogenic variants in ABCC6, is characterized by pathological ectopic calcification with poorly understood mechanisms and no effective therapies. To address this, we developed the first zebrafish model of human PXE by introducing the pathogenic ABCC6 point mutation (abcc6aR1463C/R1463C, F2 generation) using the highly efficient zhyA3A-CBE5 cytosine base editor. Three mutant types (Type1-Type3, T1-T3) stratified by calcification severity, exhibited reduced levels of the calcification inhibitors vitamin K1 (VK1) and carboxylated matrix Gla protein (cMGP), which were inversely correlated with the severity of calcification. Vertebral transcriptomics revealed dysregulated pathways related to ossification, bone remodeling-associated extracellular matrix (ECM), and immune responses, with the CXCL12-CXCR4 axis identified as a pivotal signaling hub. Early pharmacological blockade of CXCR4 using AMD3100 initiated at 5 days post-fertilization (dpf), significantly attenuated hypercalcification, whereas late intervention (from 1 month post-fertilization, mpf) demonstrated minimal efficacy. Notably, dual-target therapy combining VK1 and AMD3100 synergistically reduced hypercalcification in T3 mutants, surpassing the effects of either monotherapy. This synergy indicates functional crosstalk between vitamin K metabolism and CXCL12–CXCR4 signaling. These findings identify the CXCL12-CXCR4 axis as a therapeutic target for ectopic calcification and propose a novel dual-target strategy for PXE treatment. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-09-01 |
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| spelling | doaj-art-2d2bb0491f8f401e91e9f4e4452dcf652025-08-26T04:14:26ZengElsevierBiochemistry and Biophysics Reports2405-58082025-09-014310220410.1016/j.bbrep.2025.102204Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticumJianjian Sun0Jichang Huang1Renjie Zhang2Shubin Zhang3Tao P. Zhong4Ping Zhu5Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China; Corresponding author. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China.Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China; Corresponding author. Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China.Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China; Corresponding author. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China.Pseudoxanthoma elasticum (PXE), caused by pathogenic variants in ABCC6, is characterized by pathological ectopic calcification with poorly understood mechanisms and no effective therapies. To address this, we developed the first zebrafish model of human PXE by introducing the pathogenic ABCC6 point mutation (abcc6aR1463C/R1463C, F2 generation) using the highly efficient zhyA3A-CBE5 cytosine base editor. Three mutant types (Type1-Type3, T1-T3) stratified by calcification severity, exhibited reduced levels of the calcification inhibitors vitamin K1 (VK1) and carboxylated matrix Gla protein (cMGP), which were inversely correlated with the severity of calcification. Vertebral transcriptomics revealed dysregulated pathways related to ossification, bone remodeling-associated extracellular matrix (ECM), and immune responses, with the CXCL12-CXCR4 axis identified as a pivotal signaling hub. Early pharmacological blockade of CXCR4 using AMD3100 initiated at 5 days post-fertilization (dpf), significantly attenuated hypercalcification, whereas late intervention (from 1 month post-fertilization, mpf) demonstrated minimal efficacy. Notably, dual-target therapy combining VK1 and AMD3100 synergistically reduced hypercalcification in T3 mutants, surpassing the effects of either monotherapy. This synergy indicates functional crosstalk between vitamin K metabolism and CXCL12–CXCR4 signaling. These findings identify the CXCL12-CXCR4 axis as a therapeutic target for ectopic calcification and propose a novel dual-target strategy for PXE treatment.http://www.sciencedirect.com/science/article/pii/S2405580825002912PXEABCC6Ectopic calcificationVitamin K1CXCL12-CXCR4 axis |
| spellingShingle | Jianjian Sun Jichang Huang Renjie Zhang Shubin Zhang Tao P. Zhong Ping Zhu Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum Biochemistry and Biophysics Reports PXE ABCC6 Ectopic calcification Vitamin K1 CXCL12-CXCR4 axis |
| title | Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum |
| title_full | Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum |
| title_fullStr | Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum |
| title_full_unstemmed | Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum |
| title_short | Early pharmacological blockade of the CXCL12-CXCR4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum |
| title_sort | early pharmacological blockade of the cxcl12 cxcr4 axis attenuates vertebral hypercalcification in a zebrafish model of pseudoxanthoma elasticum |
| topic | PXE ABCC6 Ectopic calcification Vitamin K1 CXCL12-CXCR4 axis |
| url | http://www.sciencedirect.com/science/article/pii/S2405580825002912 |
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