维普中文期刊产品整合服务

Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF–RANKL signaling

查看全文 作　　者：Alexander [1,2,8]Bartelt;Friederike Behler-[1,2]Janbeck;F.Timo [1,3]Beil;Till [3,4]Koehne;Brigitte [1,2]Müller;Tobias [1,2]Schmidt;Markus [2,5]Heine;Laura [1,2]Ochs;Tayfun [3]Yilmaz;Martin [6]Dietrich;Jan [7]P.Tuckermann;Michael [3]Amling;Joachim [6]Herz;Thorsten [3]Schinke;Joerg [2]Heeren;Andreas [1,2]Niemeier 高影响力作者 机构地区：[1]Department of Orthopaedics,University Medical Center Hamburg-Eppendorf,Martinistr.52,20246 Hamburg,Germany;[2]Department of Biochemistry and Molecular Cell Biology,University Medical Center Hamburg-Eppendorf,Martinistr.52,20246 Hamburg,Germany;[3]Department of Osteology and Biomechanics,University Medical Center Hamburg-Eppendorf,Martinistr,52,20246 Hamburg,Germany;[4]Department of Orthodontics,University Medical Center Hamburg-Eppendorf,Martinistr,52 20246 Hamburg,Germany;[5]Department of Anatomy and Experimental Morphology,University Medical Center Hamburg-Eppendorf,Martinistr.52,20246 Hamburg,Germany;[6]Department of Molecular Genetics,University of Texas Southwestern Medical Center,Dallas,TX 75390,USA;[7]Institute for Comparative Molecular Endocrinology,University of Ulm,Ulm,Germany Correspondence:Andreas Niemeier;[8]Department of Genetics and Complex Diseases&Sabriülker Center,Harvard T.H.Chan School of Public Health,665 Huntington Avenue,Boston,MA 02115,USA高影响力机构 出　　处：《Bone Research》索引2018年第6卷第1期,共10页高影响力期刊 基　　金：supported by Deutsche Forschungsgemeinschaft grants to A.N. (Ni637/2-3), J.Hee. (GRK1459), to J.P.T. (Tu220/6-1, 6-2, Collaborative Research Centre 1149 ‘Trauma’ (INST 40/492-1)) as well as to M.A. and T.S. (AM103/15-2 and Schi504/5-2 within the FOR793);the Bundesministerium für Bildung und Forschung projects A Network on Clinics and Pathophysiology of Osteophytes and Ancylosis, Metabolic Impact on Joint and Bone Diseases (ANCYLOSS 01EC1002B, METARTHROS) to A.N.;Tailored Magnetic Nanoparticles for Cancer Targeting project (TOMCAT 01EZ0824) to M.H.;supported by NIH grant R37-HL63762;the Ted Nash Longlife Foundation;the Bright Focus Foundation;the Consortium for Frontotemporal Dementia Research 摘　　要：Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1(Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass.Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand(RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor(PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF–RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans. 关 键 词：PDGFRβ RANKL ACTIVATOR receptor IMATINIB axis gene vivo
相关文献

参考文献(33)

引证文献(7)

网站首页 | 关于我们 | 联系我们 | 产品服务 | 客服中心 | 广告服务 | 版权声明 | 网站联盟 | 友情链接 | 售卡网点

版权所有© 渝B2-20050021-1　渝公网安备 50019002500403号　违法和不良信息举报中心

互联网出版许可证 新出网证(渝)字10号 全国400电话 - 免长途话费