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.
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Qin
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.
authors.forename: Yuanzhen
authors.initials: Y
authors.lastname: Peng
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Harlow
authors.affiliation: Baylor College of Dentistry, Texas A&M University, Dallas, TX, USA.
authors.forename: Yinshi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department 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: Yingjie
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biology, Indiana University Purdue University, Indianapolis, IN, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Li
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Institute of Gene Engineering Animal Models for Human Diseases, Dalian Medical University, Dalian, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.
authors.forename: Shijia
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Brown
authors.affiliation: Baylor College of Dentistry, Texas A&M University, Dallas, TX, USA.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Bauman
authors.affiliation: National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Cardozo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D002452:Cell Count; D005269:Femur / Q000187:drug effects / Q000473:pathology*; D005819:Genetic Markers / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology*
chemical_list: D000906:Antibodies; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat
keywords: ANABOLICS; LRPS; OSTEOCYTES; PRECLINICAL STUDIES; STEM CELLS; STROMAL; WNT; β-CATENIN