title: Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by spinal cord injury.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA. weiping.qin@mssm.edu.|Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. weiping.qin@mssm.edu.
authors.forename: W
authors.initials: W
authors.lastname: Qin
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Peng
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Harlow
authors.affiliation: Indiana University Purdue University, Indianapolis, IN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.affiliation: Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Institute of Gene Engineering Animal Models for Human Diseases, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Gene Engineering Animal Models for Human Diseases, Dalian Medical University, Dalian, China.
authors.forename: L
authors.initials: L
authors.lastname: Ran
authors.affiliation: UCB Pharma, Slough, UK.
authors.forename: H Z
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.|Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Cardozo
authors.affiliation: National Center for the Medical Consequences of SCI, James J. Peters VA Medical Center, 130 West Kingsbridge Roa, Bronx, NY, 10468, USA.|Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Bauman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000209:etiology* / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006023:Glycoproteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D013119:Spinal Cord Injuries / Q000150:complications*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: Bone formation; Bone mineral density; Mechanical unloading; Sclerostin; Spinal cord injury; Trabecular bone volume