Targeting skeletal endothelium to ameliorate bone loss

Ren Xu; Alisha Yallowitz; An Qin; Zhuhao Wu; Dong Yeon Shin; Jung Min Kim; Shawon Debnath; Gang Ji; Mathias P. Bostrom; Xu Yang; Chao Zhang; Han Dong; Pouneh Kermani; Sarfaraz Lalani; Na Li; Yifang Liu; Michael G. Poulos; Amanda Wach; Yi Zhang; Kazuki Inoue; Annarita Di Lorenzo; Baohong Zhao; Jason M. Butler; Jae Hyuck Shim; Laurie H. Glimcher; Matthew B. Greenblatt

doi:10.1038/s41591-018-0020-z

Targeting skeletal endothelium to ameliorate bone loss

Ren Xu, Alisha Yallowitz, An Qin, Zhuhao Wu, Dong Yeon Shin, Jung Min Kim, Shawon Debnath, Gang Ji, Mathias P. Bostrom, Xu Yang, Chao Zhang, Han Dong, Pouneh Kermani, Sarfaraz Lalani, Na Li, Yifang Liu, Michael G. Poulos, Amanda Wach, Yi Zhang, Kazuki InoueAnnarita Di Lorenzo, Baohong Zhao, Jason M. Butler, Jae Hyuck Shim, Laurie H. Glimcher, Matthew B. Greenblatt

Research output: Contribution to journal › Article › peer-review

256 Scopus citations

Abstract

Recent studies have identified a specialized subset of CD31^hiendomucin^hi (CD31^hiEMCN^hi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31^hiEMCN^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^hiEMCN^hi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31^hiEMCN^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 osteoblasts and CD31^hiEMCN^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.

Original language	English
Pages (from-to)	823-833
Number of pages	11
Journal	Nature Medicine
Volume	24
Issue number	6
DOIs	https://doi.org/10.1038/s41591-018-0020-z
State	Published - 1 Jun 2018
Externally published	Yes

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Xu, R., Yallowitz, A., Qin, A., Wu, Z., Shin, D. Y., Kim, J. M., Debnath, S., Ji, G., Bostrom, M. P., Yang, X., Zhang, C., Dong, H., Kermani, P., Lalani, S., Li, N., Liu, Y., Poulos, M. G., Wach, A., Zhang, Y., ... Greenblatt, M. B. (2018). Targeting skeletal endothelium to ameliorate bone loss. Nature Medicine, 24(6), 823-833. https://doi.org/10.1038/s41591-018-0020-z

@article{11e04babe26f46d29f7c51a12aa19658,

title = "Targeting skeletal endothelium to ameliorate bone loss",

abstract = "Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi 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 CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi 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 osteoblasts and CD31hiEMCNhi 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.",

author = "Ren Xu and Alisha Yallowitz and An Qin and Zhuhao Wu and Shin, {Dong Yeon} and Kim, {Jung Min} and Shawon Debnath and Gang Ji and Bostrom, {Mathias P.} and Xu Yang and Chao Zhang and Han Dong and Pouneh Kermani and Sarfaraz Lalani and Na Li and Yifang Liu and Poulos, {Michael G.} and Amanda Wach and Yi Zhang and Kazuki Inoue and {Di Lorenzo}, Annarita and Baohong Zhao and Butler, {Jason M.} and Shim, {Jae Hyuck} and Glimcher, {Laurie H.} and Greenblatt, {Matthew B.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41591-018-0020-z",

language = "English",

volume = "24",

pages = "823--833",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

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Xu, R, Yallowitz, A, Qin, A, Wu, Z, Shin, DY, Kim, JM, Debnath, S, Ji, G, Bostrom, MP, Yang, X, Zhang, C, Dong, H, Kermani, P, Lalani, S, Li, N, Liu, Y, Poulos, MG, Wach, A, Zhang, Y, Inoue, K, Di Lorenzo, A, Zhao, B, Butler, JM, Shim, JH, Glimcher, LH & Greenblatt, MB 2018, 'Targeting skeletal endothelium to ameliorate bone loss', Nature Medicine, vol. 24, no. 6, pp. 823-833. https://doi.org/10.1038/s41591-018-0020-z

TY - JOUR

T1 - Targeting skeletal endothelium to ameliorate bone loss

AU - Xu, Ren

AU - Yallowitz, Alisha

AU - Qin, An

AU - Wu, Zhuhao

AU - Shin, Dong Yeon

AU - Kim, Jung Min

AU - Debnath, Shawon

AU - Ji, Gang

AU - Bostrom, Mathias P.

AU - Yang, Xu

AU - Zhang, Chao

AU - Dong, Han

AU - Kermani, Pouneh

AU - Lalani, Sarfaraz

AU - Li, Na

AU - Liu, Yifang

AU - Poulos, Michael G.

AU - Wach, Amanda

AU - Zhang, Yi

AU - Inoue, Kazuki

AU - Di Lorenzo, Annarita

AU - Zhao, Baohong

AU - Butler, Jason M.

AU - Shim, Jae Hyuck

AU - Glimcher, Laurie H.

AU - Greenblatt, Matthew B.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi 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 CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi 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 osteoblasts and CD31hiEMCNhi 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.

AB - Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi 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 CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi 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 osteoblasts and CD31hiEMCNhi 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.

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U2 - 10.1038/s41591-018-0020-z

DO - 10.1038/s41591-018-0020-z

M3 - Article

C2 - 29785024

AN - SCOPUS:85047216276

SN - 1078-8956

VL - 24

SP - 823

EP - 833

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

Targeting skeletal endothelium to ameliorate bone loss

Abstract

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