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Osteoporosis International

, Volume 27, Issue 12, pp 3627–3636 | Cite as

Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by spinal cord injury

  • W. QinEmail author
  • W. Zhao
  • X. Li
  • Y. Peng
  • L. M. Harlow
  • J. Li
  • Y. Qin
  • J. Pan
  • Y. Wu
  • L. Ran
  • H. Z. Ke
  • C. P. Cardozo
  • W. A. Bauman
Original Article

Abstract

Summary

Bone loss after spinal cord injury (SCI) is rapid, severe, and refractory to interventions studied to date. Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by SCI, further indicating pharmacological inhibition of sclerostin may represent a promising novel approach to this challenging medical problem.

Introduction

The bone loss secondary to spinal cord injury (SCI) is associated with several unique pathological features, including the permanent immobilization, neurological dysfunction, and systemic hormonal alternations. It remains unclear how these complex pathophysiological changes are linked to molecular alterations that influence bone metabolism in SCI. Sclerostin is a key negative regulator of bone formation and bone mass. We hypothesized that sclerostin could function as a major mediator of bone loss following SCI.

Methods

To test this hypothesis, 10-week-old female sclerostin knockout (SOST KO) and wild type (WT) mice underwent complete spinal cord transection or laminectomy (Sham).

Results

At 8 weeks after SCI, substantial loss of bone mineral density was observed at the distal femur and proximal tibia in WT mice but not in SOST KO mice. By μCT, trabecular bone volume of the distal femur was markedly decreased by 64 % in WT mice after SCI. In striking contrast, there was no significant reduction of bone volume in SOST KO/SCI mice compared with SOST KO/sham. Histomorphometric analysis of trabecular bone revealed that the significant reduction in bone formation rate following SCI was observed in WT mice but not in SOST KO mice. Moreover, SCI did not alter osteoblastogenesis of marrow stromal cells in SOST KO mice.

Conclusion

Our findings demonstrate that SOST KO mice were protected from the major sublesional bone loss that invariably follows SCI. The evidence indicates that sclerostin is an important mediator of the marked sublesional bone loss after SCI, and that pharmacological inhibition of sclerostin may represent a promising novel approach to this challenging clinical problem.

Keywords

Bone formation Bone mineral density Mechanical unloading Sclerostin Spinal cord injury Trabecular bone volume 

Abbreviations

BFR

Bone formation rate

BMD

Bone mineral density

CFU-F

Colony-forming unit-fibroblastic

DXA

Dual-energy x-ray absorptiometer

KO

Knockout

MAR

Mineral apposition rate

MS/BS

Mineralizing surface/bone surface

MSCs

Mesenchymal stem cells

PFA

Paraformyldahyde

SCI

Spinal cord injury

SOST

Sclerostin

Notes

Acknowledgments

This work was supported by the Veterans Health Administration, Rehabilitation Research, and Development Service (grants 5I01RX001313 and 5I01RX000687 to WQ; B9212-C and B2020-C to WAB). Ministry of Science and Technology PRC grant 2014DFA32120 and the Natural Science Foundation of China (NSFC) grant 81471000 to YW. Amgen Inc. provided SOST KO mice. Authors’ roles: CPC, HK, XL, WAB, and WQ were responsible for study design and data analysis. YP, LH, WZ, JL, YQ, YW, LR, and WQ conducted the bone biology study. Jay Cao performed microCT analysis. The manuscript was written by WZ and WQ and was revised and approved by all authors. WQ takes responsibility for the integrity of the data analysis.

Compliance with ethical standards

Competing interests

Yuanzhen Peng, Wei Zhao, Xiaodong Li, Lauren M Harlow, Jiliang Li, Yiwen Qin, Jianping Pan, Yingjie Wu, Liyuan Ran, Hua Zhu Ke, William A. Bauman, Christopher Cardozo, and Weiping Qin declare that they have no conflict of interest.

Disclosure

YP, WZ, LH, JL, YQ, JP, YW, LR, CPC, WAB, and WQ have nothing to disclose. XL is current employee and shareholder of Amgen Inc., and HZK is current employee and shareholder of UCB Pharma.

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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2016

Authors and Affiliations

  • W. Qin
    • 1
    • 2
    Email author
  • W. Zhao
    • 1
  • X. Li
    • 5
  • Y. Peng
    • 1
  • L. M. Harlow
    • 1
  • J. Li
    • 6
  • Y. Qin
    • 1
  • J. Pan
    • 1
  • Y. Wu
    • 2
    • 7
  • L. Ran
    • 7
  • H. Z. Ke
    • 8
  • C. P. Cardozo
    • 1
    • 2
    • 3
    • 4
  • W. A. Bauman
    • 1
    • 2
    • 3
  1. 1.National Center for the Medical Consequences of SCI, James J. Peters VA Medical CenterBronxUSA
  2. 2.Departments of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Rehabilitation MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Pharmacology and Systems TherapeuticsIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Amgen IncThousand OaksUSA
  6. 6.Indiana University Purdue UniversityIndianapolisUSA
  7. 7.Institute of Gene Engineering Animal Models for Human DiseasesDalian Medical UniversityDalianChina
  8. 8.UCB PharmaSloughUK

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