Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats

Weiping Qin, Xiaodong Li, Yuanzhen Peng, Lauren M. Harlow, Yinshi Ren, Yingjie Wu, Jiliang Li, Yiwen Qin, Jie Sun, Shijia Zheng, Tom Brown, Jian Q. Feng, Hua Zhu Ke, William A. Bauman, Christopher C. Cardozo

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25%) and trabecular bone volume (-67%) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders.

Original languageEnglish (US)
Pages (from-to)1994-2004
Number of pages11
JournalJournal of Bone and Mineral Research
Volume30
Issue number11
DOIs
StatePublished - Nov 2015
Externally publishedYes

Fingerprint

Osteocytes
Spinal Cord Injuries
Antibodies
Bone and Bones
Osteoprotegerin
Osteogenesis
Messenger RNA
Bone Remodeling
Dendrites
Nervous System Diseases
Bone Marrow Cells
Electron Scanning Microscopy
Bone Density
Femur
Osteoporosis

Keywords

  • ANABOLICS
  • LRPS
  • OSTEOCYTES
  • PRECLINICAL STUDIES
  • STEM CELLS
  • STROMAL
  • WNT
  • β-CATENIN

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats. / Qin, Weiping; Li, Xiaodong; Peng, Yuanzhen; Harlow, Lauren M.; Ren, Yinshi; Wu, Yingjie; Li, Jiliang; Qin, Yiwen; Sun, Jie; Zheng, Shijia; Brown, Tom; Feng, Jian Q.; Ke, Hua Zhu; Bauman, William A.; Cardozo, Christopher C.

In: Journal of Bone and Mineral Research, Vol. 30, No. 11, 11.2015, p. 1994-2004.

Research output: Contribution to journalArticle

Qin, W, Li, X, Peng, Y, Harlow, LM, Ren, Y, Wu, Y, Li, J, Qin, Y, Sun, J, Zheng, S, Brown, T, Feng, JQ, Ke, HZ, Bauman, WA & Cardozo, CC 2015, 'Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats', Journal of Bone and Mineral Research, vol. 30, no. 11, pp. 1994-2004. https://doi.org/10.1002/jbmr.2549
Qin, Weiping ; Li, Xiaodong ; Peng, Yuanzhen ; Harlow, Lauren M. ; Ren, Yinshi ; Wu, Yingjie ; Li, Jiliang ; Qin, Yiwen ; Sun, Jie ; Zheng, Shijia ; Brown, Tom ; Feng, Jian Q. ; Ke, Hua Zhu ; Bauman, William A. ; Cardozo, Christopher C. / Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats. In: Journal of Bone and Mineral Research. 2015 ; Vol. 30, No. 11. pp. 1994-2004.
@article{23d4daf2ff7e4fefbab4bf3c4148b5eb,
title = "Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats",
abstract = "Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25{\%}) and trabecular bone volume (-67{\%}) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders.",
keywords = "ANABOLICS, LRPS, OSTEOCYTES, PRECLINICAL STUDIES, STEM CELLS, STROMAL, WNT, β-CATENIN",
author = "Weiping Qin and Xiaodong Li and Yuanzhen Peng and Harlow, {Lauren M.} and Yinshi Ren and Yingjie Wu and Jiliang Li and Yiwen Qin and Jie Sun and Shijia Zheng and Tom Brown and Feng, {Jian Q.} and Ke, {Hua Zhu} and Bauman, {William A.} and Cardozo, {Christopher C.}",
year = "2015",
month = "11",
doi = "10.1002/jbmr.2549",
language = "English (US)",
volume = "30",
pages = "1994--2004",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "11",

}

TY - JOUR

T1 - Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats

AU - Qin, Weiping

AU - Li, Xiaodong

AU - Peng, Yuanzhen

AU - Harlow, Lauren M.

AU - Ren, Yinshi

AU - Wu, Yingjie

AU - Li, Jiliang

AU - Qin, Yiwen

AU - Sun, Jie

AU - Zheng, Shijia

AU - Brown, Tom

AU - Feng, Jian Q.

AU - Ke, Hua Zhu

AU - Bauman, William A.

AU - Cardozo, Christopher C.

PY - 2015/11

Y1 - 2015/11

N2 - Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25%) and trabecular bone volume (-67%) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders.

AB - Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25%) and trabecular bone volume (-67%) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders.

KW - ANABOLICS

KW - LRPS

KW - OSTEOCYTES

KW - PRECLINICAL STUDIES

KW - STEM CELLS

KW - STROMAL

KW - WNT

KW - β-CATENIN

UR - http://www.scopus.com/inward/record.url?scp=84945496080&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945496080&partnerID=8YFLogxK

U2 - 10.1002/jbmr.2549

DO - 10.1002/jbmr.2549

M3 - Article

C2 - 25974843

AN - SCOPUS:84945496080

VL - 30

SP - 1994

EP - 2004

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 11

ER -