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J Bone Miner Res. 2015 Nov;30(11):1994-2004. doi: 10.1002/jbmr.2549. Epub 2015 Jun 10.

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

Author information

1
National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA.
2
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Amgen Inc., Thousand Oaks, CA, USA.
4
Baylor College of Dentistry, Texas A&M University, Dallas, TX, USA.
5
Institute of Gene Engineering Animal Models for Human Diseases, Dalian Medical University, Dalian, China.
6
Department of Biology, Indiana University Purdue University, Indianapolis, IN, USA.
7
Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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

PMID:
25974843
DOI:
10.1002/jbmr.2549
[Indexed for MEDLINE]
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