Longitudinal Examination of Bone Loss in Male Rats After Moderate–Severe Contusion Spinal Cord Injury
To elucidate mechanisms of bone loss after spinal cord injury (SCI), we evaluated the time-course of cancellous and cortical bone microarchitectural deterioration via microcomputed tomography, measured histomorphometric and circulating bone turnover indices, and characterized the development of whole bone mechanical deficits in a clinically relevant experimental SCI model. 16-weeks-old male Sprague–Dawley rats received T9 laminectomy (SHAM, n = 50) or moderate–severe contusion SCI (n = 52). Outcomes were assessed at 2-weeks, 1-month, 2-months, and 3-months post-surgery. SCI produced immediate sublesional paralysis and persistent hindlimb locomotor impairment. Higher circulating tartrate-resistant acid phosphatase 5b (bone resorption marker) and lower osteoblast bone surface and histomorphometric cancellous bone formation indices were present in SCI animals at 2-weeks post-surgery, suggesting uncoupled cancellous bone turnover. Distal femoral and proximal tibial cancellous bone volume, trabecular thickness, and trabecular number were markedly lower after SCI, with the residual cancellous network exhibiting less trabecular connectivity. Periosteal bone formation indices were lower at 2-weeks and 1-month post-SCI, preceding femoral cortical bone loss and the development of bone mechanical deficits at the distal femur and femoral diaphysis. SCI animals also exhibited lower serum testosterone than SHAM, until 2-months post-surgery, and lower serum leptin throughout. Our moderate–severe contusion SCI model displayed rapid cancellous bone deterioration and more gradual cortical bone loss and development of whole bone mechanical deficits, which likely resulted from a temporal uncoupling of bone turnover, similar to the sequalae observed in the motor-complete SCI population. Low testosterone and/or leptin may contribute to the molecular mechanisms underlying bone deterioration after SCI.
KeywordsOsteoporosis Bone mineral density Disuse Testosterone Leptin Sclerostin
This work was supported by the Office of Research and Development, Rehabilitation Research and Development (RR&D) Service, Department of Veterans Affairs (SPiRE 1I21RX001273-01 and PECASE #B9280-O) to JFY, and by resources provided by the North Florida/South Georgia Veterans Health System. The work reported herein does not represent the views of the US Department of Veterans Affairs or the US Government.
Compliance with Ethical Standards
Conflict of interest
Dana M. Otzel, Christine F. Conover, Fan Ye, Ean G. Phillips, Taylor Bassett, Russell D. Wnek, Micah Flores, Andrea Catter, Payal Ghosh, Alexander Balaez, Jason Petusevsky, Cong Chen, Yongxin Gao, Yi Zhang, Jessica M. Jiron, Prodip K. Bose, Stephen E. Borst, Thomas J. Wronski, J. Ignacio Aguirre and Joshua F. Yarrow declares that they have no conflict of interest.
Human and Animal Rights and Informed Consent
All experimental procedures conformed to the ILAR Guide to the Care and Use of Experimental Animals and were approved by the Institutional Animal Care and Use Committee at the Malcom Randall VA Medical Center.
- 24.Yarrow JF, Conover CF, Purandare AV, Bhakta AM, Zheng N, Conrad B, Altman MK, Franz SE, Wronski TJ, Borst SE (2008) Supraphysiological testosterone enanthate administration prevents bone loss and augments bone strength in gonadectomized male and female rats. Am J Physiol Endocrinol Metab 295(5):E1213–E1222CrossRefPubMedGoogle Scholar
- 31.Han B, Copeland M, Geiser AG, Hale LV, Harvey A, Ma YL, Powers CS, Sato M, You J, Hale JE (2007) Development of a highly sensitive, high-throughput, mass spectrometry-based assay for rat procollagen type-I N-terminal propeptide (PINP) to measure bone formation activity. J Proteome Res 6(11):4218–4229CrossRefPubMedGoogle Scholar
- 37.Phillips EG, Beggs LA, Ye F, Conover CF, Beck DT, Otzel DM, Ghosh P, Bassit ACF, Borst SE, Yarrow JF (2018) Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury. PLoS ONE 13(3):e0194440CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Gifre L, Vidal J, Carrasco JL, Filella X, Ruiz-Gaspa S, Muxi A, Portell E, Monegal A, Guanabens N, Peris P (2015) Effect of recent spinal cord injury on wnt signaling antagonists (sclerostin and dkk-1) and their relationship with bone loss. A 12-month prospective study. J Bone Miner Res 30(6):1014–1021CrossRefPubMedGoogle Scholar
- 48.Samantaray S, Das A, Matzelle DC, Yu SP, Wei L, Varma A, Ray SK, Banik NL (2016) Administration of low dose estrogen attenuates persistent inflammation, promotes angiogenesis, and improves locomotor function following chronic spinal cord injury in rats. J Neurochem 137(4):604–617CrossRefPubMedPubMedCentralGoogle Scholar