索拉非尼通过阻断 LOXL2 介导的血管生成抑制后纵韧带骨化

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Longqing Wang, Wenhao Jiang, Siyuan Zhao, Dong Xie, Qing Chen, Qi Zhao, Hao Wu, Jian Luo, Lili Yang
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引用次数: 0

摘要

后纵韧带骨化(OPLL)是一种退行性骨质疏松疾病,其特点是柔软而富有弹性的椎韧带转变为骨质,导致脊柱活动受限和神经受压。我们采用大量和单细胞 RNA 测序技术,以单细胞分辨率阐明了 OPLL 过程中的分子特征、细胞成分及其演变,并在临床样本中验证了这些发现。这项研究还揭示了韧带干细胞在体外和体内表现出内皮细胞样表型的能力。值得注意的是,我们的研究发现LOXL2是这一过程中的关键调节因子。通过功能增益和功能缺失研究,我们阐明了LOXL2在韧带细胞内皮样分化中的作用。它通过 HIF1A 途径发挥作用,促进下游 VEGFA 和 PDGF-BB 的分泌。这一功能与 LOXL2 的酶活性无关。此外,我们还发现索拉非尼(一种广谱酪氨酸激酶抑制剂)能有效抑制 LOXL2 介导的血管形态发生。通过破坏血管形成和骨生成之间的耦合,索拉非尼在BMP诱导和enpp1缺乏诱导的动物模型中都能显著抑制OPLL的进展,同时对正常骨量没有明显影响。这些发现强调了索拉非尼作为OPLL治疗干预措施的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization

Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization

Ossification of the Posterior Longitudinal Ligament (OPLL) is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone, resulting in limited spinal mobility and nerve compression. Employing both bulk and single-cell RNA sequencing, we elucidate the molecular characteristics, cellular components, and their evolution during the OPLL process at a single-cell resolution, and validate these findings in clinical samples. This study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in vivo. Notably, our study identifies LOXL2 as a key regulator in this process. Through gain-and loss-of-function studies, we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament cells. It acts via the HIF1A pathway, promoting the secretion of downstream VEGFA and PDGF-BB. This function is not related to the enzymatic activity of LOXL2. Furthermore, we identify sorafenib, a broad-spectrum tyrosine kinase inhibitor, as an effective suppressor of LOXL2-mediated vascular morphogenesis. By disrupting the coupling between vascularization and osteogenesis, sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone mass. These findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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