Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease(GSD)mouse model  

作　　者：Dongfang ZHANG Hao XU Chi QIN Kangming CAI Jing ZHANG Xinqiu XIA Jingwen BI Li ZHANG Lianping XING Qianqian LIANG Wensheng WANG 

机构地区：[1]Laboratory of Molecular Medicine,College of Life Science and State Key Laboratory of Cell Differentiation and Regulation,Henan Normal University,Xinxiang,453007,China [2]Longhua Hospital&Spine Institute,Shanghai University of Traditional Chinese Medicine,Shanghai,200032,China [3]Key Laboratory of Theory and Therapy of Muscles and Bones,Ministry of Education(Shanghai University of Traditional Chinese Medicine),Shanghai,201203,China [4]Department of Pathology and Laboratory Medicine,University of Rochester Medical Center,Rochester,14642,USA

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2024年第1期38-50,共13页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the National Natural Science Foundation of China(No.81974321);the Discipline Innovation and Talent Introduction Program to Universities from Ministry of Education of China(Project 111);the Tackling Project for Science and Technology of Xinxiang City(No.GG2019003);the Natural Science Foundation of Henan Province of China(No.212300410173);the State Administration of Traditional Chinese Medicine Young Qi Huang Scholar,and the Innovation Team Project of Scientific Research of Traditional Chinese Medicine of Shanghai Health Committee(No.2022CX001);China.

摘　　要：Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow cavities.Although the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely investigated.In this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of GSD.Compared to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in OCPs.In the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in vitro.Using an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo.We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like phenotypes.Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the control.Based on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

关 键 词：Semaphorin 3A Gorham-Stout disease OSTEOCLAST OSTEOLYSIS Lymphatic endothelial cell 

分 类 号：R681[医药卫生—骨科学]