Sun Jianjian, Huang Jichang, Zhang Renjie, Zhang Shubin, Zhong Tao P, Zhu Ping
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.
Biochem Biophys Rep. 2025 Aug 25;43:102204. doi: 10.1016/j.bbrep.2025.102204. eCollection 2025 Sep.
Pseudoxanthoma elasticum (PXE), caused by pathogenic variants in , 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 point mutation ( , 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.
弹性假黄瘤（PXE）由[基因名称]的致病变异引起，其特征为病理性异位钙化，机制尚不清楚且无有效治疗方法。为解决这一问题，我们通过使用高效的zhyA3A - CBE5胞嘧啶碱基编辑器引入致病性点突变（[具体突变内容]，F2代），开发了首个人类PXE斑马鱼模型。根据钙化严重程度分层的三种突变类型（1型 - 3型，T1 - T3），钙化抑制剂维生素K1（VK1）和羧化基质Gla蛋白（cMGP）水平降低，且与钙化严重程度呈负相关。脊椎转录组学揭示了与骨化、骨重塑相关的细胞外基质（ECM）和免疫反应相关的失调途径，其中CXCL12 - CXCR4轴被确定为关键信号枢纽。在受精后5天（dpf）开始使用AMD3100对CXCR4进行早期药理阻断，可显著减轻过度钙化，而后期干预（从受精后1个月，mpf开始）效果甚微。值得注意的是，VK1和AMD3100联合双靶点治疗协同降低了T3突变体中的过度钙化，超过了单一疗法的效果。这种协同作用表明维生素K代谢与CXCL12 - CXCR4信号之间存在功能相互作用。这些发现确定CXCL12 - CXCR4轴为异位钙化的治疗靶点，并提出了一种新的PXE治疗双靶点策略。
