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

作　　者：Longqing Wang Wenhao Jiang Siyuan Zhao Dong Xie Qing Chen Qi Zhao Hao Wu Jian Luo Lili Yang 

机构地区：[1]Spine Center,Department of Orthopaedics,Shanghai Changzheng Hospital,Second Affiliated Hospital of Naval Medical University,Shanghai 200003,PR China [2]Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center),Tongji University School of Medicine,Shanghai,PR China [3]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai,PR China [4]Department of Orthopaedics,No.905 Hospital of PLA Navy,Shanghai,PR China

出　　处：《Bone Research》2024年第2期372-389,共18页骨研究（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82372431 to L.L.Y.,92168204 and 82225030 to J.L.);the Shanghai Municipal Health Commission(2022LJ007 to L.L.Y.);the Science and Technology Commission of Shanghai Municipality(22ZR1476700 to L.L.Y.);Shanghai Municipal Annual Innovative Medical Device Application Demonstration Project(23SHS05700-06 to L.L.Y.);the Fifth Round Innovation Team of Shanghai Changning District(to L.L.Y.);“Open bidding for selecting the best candidates”cultivation project of Shanghai Changzheng Hospital(2023YJBF-PY10 to L.L.Y.).

摘　　要：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.

关 键 词：LOXL2 LIGAMENT finding 

分 类 号：R681[医药卫生—骨科学]