Aims Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients with cardiovascular disease. Matrix metalloproteinase 3 (MMP-3), also known as stromelysin-1, is part of the large matrix metalloproteinase family. It can degrade extracellular matrix components of the arterial wall including elastin, which plays a central role in medial calcification. In this study, we sought to determine the role of MMP-3 in medial calcification. Methods and Results We found that MMP-3 was increased in rodent models of medial calcification as well as in vascular smooth muscle cells (SMCs) cultured in a phosphate calcification medium. It was also highly expressed in calcified tibial arteries from patients with peripheral arterial disease (PAD). Knockdown and inhibition of MMP-3 suppressed phosphate-induced SMC osteogenic transformation and calcification, whereas the addition of a recombinant MMP-3 protein facilitated SMC calcification. In an ex vivo organ culture model and a rodent model of medial calcification induced by vitamin D3, we found that MMP-3 deficiency significantly suppressed medial calcification in the aorta. We further found that medial calcification and osteogenic transformation were significantly reduced in SMC-specific MMP-3-deficient mice, suggesting that MMP-3 in SMCs is an important factor in this process. Conclusion These findings suggest that MMP-3 expression in vascular SMCs is an important regulator of medial calcification and that targeting MMP-3 could provide a therapeutic strategy to reduce it and address its consequences in patients with PAD.

中文翻译：

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平滑肌细胞特异性 MMP-3 缺失减少成骨转化和内侧动脉钙化

目的 血管钙化在动脉粥样硬化、糖尿病和慢性肾病中非常普遍。它与心血管疾病患者发病率和死亡率的增加有关。基质金属蛋白酶 3 (MMP-3)，也称为 Stromelysin-1，是大基质金属蛋白酶家族的一部分。它可以降解动脉壁的细胞外基质成分，包括弹性蛋白，弹性蛋白在内侧钙化中起着核心作用。在本研究中，我们试图确定 MMP-3 在内侧钙化中的作用。方法和结果我们发现，在内侧钙化的啮齿动物模型以及在磷酸盐钙化培养基中培养的血管平滑肌细胞（SMC）中，MMP-3 增加。它在外周动脉疾病（PAD）患者的钙化胫骨动脉中也高表达。MMP-3 的敲低和抑制抑制了磷酸盐诱导的 SMC 成骨转化和钙化，而添加重组 MMP-3 蛋白则促进 SMC 钙化。在离体器官培养模型和维生素 D3 诱导的内侧钙化啮齿动物模型中，我们发现 MMP-3 缺乏显着抑制主动脉内侧钙化。我们进一步发现，在 SMC 特异性 MMP-3 缺陷小鼠中，内侧钙化和成骨转化显着减少，表明 SMC 中的 MMP-3 是这一过程的重要因素。结论 这些研究结果表明，血管 SMC 中的 MMP-3 表达是内侧钙化的重要调节因子，针对 MMP-3 可以提供一种治疗策略，以减少 MMP-3 的表达并解决其对 PAD 患者的影响。