Targeting skeletal endothelium to ameliorate bone loss

被引：398

作者：

Xu, Ren ^{[1
]}

Yallowitz, Alisha ^{[1
]}

Qin, An ^{[2
]}

Wu, Zhuhao ^{[3
]}

Shin, Dong Yeon ^{[1
]}

Kim, Jung-Min ^{[4
]}

Debnath, Shawon ^{[1
]}

Ji, Gang ^{[5
,6
]}

Bostrom, Mathias P. ^{[5
,7
]}

Yang, Xu ^{[5
]}

Zhang, Chao ^{[8
]}

Dong, Han ^{[9
,10
,11
,12
]}

Kermani, Pouneh ^{[13
]}

Lalani, Sarfaraz ^{[1
]}

Li, Na ^{[1
]}

Liu, Yifang ^{[1
]}

Poulos, Michael G. ^{[13
]}

Wach, Amanda ^{[14
]}

Zhang, Yi ^{[1
]}

Inoue, Kazuki ^{[15
,16
,17
]}

Di Lorenzo, Annarita ^{[1
]}

Zhao, Baohong ^{[15
,16
,17
]}

Butler, Jason M. ^{[13
]}

Shim, Jae-Hyuck ^{[4
]}

Glimcher, Laurie H. ^{[9
,10
,11
,12
]}

Greenblatt, Matthew B. ^{[1
]}

机构：

[1] Cornell Univ, Dept Pathol & Lab Med, New York, NY 10021 USA

[2] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Dept Orthopaed, Shanghai Key Lab Orthopaed Implant,Sch Med, Shanghai, Peoples R China

[3] Rockefeller Univ, Lab Brain Dev & Repair, 1230 York Ave, New York, NY 10021 USA

[4] Univ Massachusetts, Dept Med, Med Sch, Div Rheumatol, Worcester, MA USA

[5] Hosp Special Surg, Res Div, 535 E 70th St, New York, NY 10021 USA

[6] Hebei Med Univ, Dept Joint Surg, Hosp 3, Shijiazhuang, Hebei, Peoples R China

[7] Hosp Special Surg, Div Adult Reconstruct & Joint Replacement, Dept Orthopaed Surg, 535 E 70th St, New York, NY 10021 USA

[8] Cornell Univ, Inst Computat Biomed, New York, NY 10021 USA

[9] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA

[10] Harvard Univ, Med Sch, Boston, MA 02115 USA

[11] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[12] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA

[13] Cornell Univ, Ansary Stem Cell Inst, Dept Med, Div Regenerat Med, New York, NY 10021 USA

[14] Hosp Special Surg, Dept Biomech, 535 E 70th St, New York, NY 10021 USA

[15] Hosp Special Surg, Arthrit & Tissue Degenerat Program, 535 E 70th St, New York, NY 10021 USA

[16] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, 535 E 70th St, New York, NY 10021 USA

[17] Cornell Univ, Weill Cornell Med Coll, Dept Med, New York, NY 10021 USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 06期

关键词：

OSTEOBLAST DIFFERENTIATION; VASCULAR NETWORK; ANGIOGENESIS; ROBO; SLIT2; OSTEOGENESIS; MAINTENANCE; EXPRESSION; ROLES; MICE;

D O I：

10.1038/s41591-018-0020-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Recent studies have identified a specialized subset of CD31(hi)endomucin(hi) (CD31(hi)EMCN(hi)) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31(hi)EMCN(hi) endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31(hi)EMCN(hi) endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31(hi)EMCN(hi) endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3(-/-) mice. This coupling between osteo-blasts and CD31(hi)EMCN(hi) endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.

引用

页码：823 / +

页数：13

共 51 条

[1]

Slit2-mediated chemorepulsion and collapse of developing forebrain axons [J].

Ba-Charvet, KTN ;

Brose, K ;

Marillat, V ;

Kidd, T ;

Goodman, CS ;

Tessier-Lavigne, M ;

Sotelo, C ;

Chédotal, A .

NEURON, 1999, 22 (03) :463-473

[2]

Slit-Robo signaling [J].

Blockus, Heike ;

Chedotal, Alain .

DEVELOPMENT, 2016, 143 (17) :3037-3044

[3]

Ovariectomy-induced bone loss varies among inbred strains of mice [J].

Bouxsein, ML ;

Myers, KS ;

Shultz, KL ;

Donahue, LR ;

Rosen, CJ ;

Beamer, WG .

JOURNAL OF BONE AND MINERAL RESEARCH, 2005, 20 (07) :1085-1092

[4]

The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice [J].

Bradaschia-Correa, Vivian ;

Josephson, Anne M. ;

Mehta, Devan ;

Mizrahi, Matthew ;

Neibart, Shane S. ;

Liu, Chao ;

Kennedy, Oran D. ;

Castillo, Alesha B. ;

Egol, Kenneth A. ;

Leucht, Philipp .

JOURNAL OF BONE AND MINERAL RESEARCH, 2017, 32 (04) :821-833

[5]

Bone healing in 2016 [J].

Buza, John A., III ;

Einhorn, Thomas .

CLINICAL CASES IN MINERAL AND BONE METABOLISM, 2016, 13 (02) :101-105

[6]

Chen JQ, 2014, PLOS ONE, V9, DOI [10.1371/journal.pone.0101277, 10.1371/journal.pone.0085161]

[7]

Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter [J].

Chen, Michael J. ;

Yokomizo, Tomomasa ;

Zeigler, Brandon M. ;

Dzierzak, Elaine ;

Speck, Nancy A. .

NATURE, 2009, 457 (7231) :887-891

[8]

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2 [J].

Choi, Hyun-Jung ;

Zhang, Haiying ;

Park, Hongryeol ;

Choi, Kyu-Sung ;

Lee, Heon-Woo ;

Agrawal, Vijayendra ;

Kim, Young-Myeong ;

Kwon, Young-Guen .

NATURE COMMUNICATIONS, 2015, 6

[9]

Standardized Nomenclature, Symbols, and Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR Histomorphometry Nomenclature Committee [J].

Dempster, David W. ;

Compston, Juliet E. ;

Drezner, Marc K. ;

Glorieux, Francis H. ;

Kanis, John A. ;

Malluche, Hartmut ;

Meunier, Pierre J. ;

Ott, Susan M. ;

Recker, Robert R. ;

Parfitt, A. Michael .

JOURNAL OF BONE AND MINERAL RESEARCH, 2013, 28 (01) :1-16

[10]

STAR: ultrafast universal RNA-seq aligner [J].

Dobin, Alexander ;

Davis, Carrie A. ;

Schlesinger, Felix ;

Drenkow, Jorg ;

Zaleski, Chris ;

Jha, Sonali ;

Batut, Philippe ;

Chaisson, Mark ;

Gingeras, Thomas R. .

BIOINFORMATICS, 2013, 29 (01) :15-21

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