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.
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.).
作者简介
Correspondence:Jian Luo(jluo@tongji.edu.cn);Correspondence:Lili Yang(yangll@smmu.edu.cn);Longqing Wang,contributed equally;Wenhao Jiang,contributed equally。
