Severe Spinal Cord Injury Causes Immediate Multi-cellular Dysfunction at the Chondro-Osseous Junction

Abstract

Spinal cord injury is associated with rapid bone loss and arrested long bone growth due to mechanisms that are poorly understood. In this study, we sought to determine the effects of severe T10 contusion spinal cord injury on the sublesional bone microenvironment in adolescent rats. A severe lower thoracic (vertebral T10) spinal cord injury was generated by weight drop (10 g×50 mm). Severely injured and body weight-matched uninjured male Sprague–Dawley rats were studied. At 3 and 5 days post-injury, we performed histological analysis of the distal femoral metaphysis, TUNEL assay, immunohistochemistry, real-time PCR, and western blot analysis compared to uninjured controls. We observed severe hindlimb functional deficits typical of this model. We detected uncoupled remodeling with increased osteoclast activity in the absence of osteoblast activity. We detected osteoblast, osteocyte, and chondrocyte apoptosis with suppressed osteoblast and chondrocyte proliferation and growth plate arrest due to spinal cord injury. We also detected altered gene expression in both whole bone extracts and bone marrow monocytes following spinal cord injury. We conclude that spinal cord injury results in altered gene expression of key regulators of osteoblast and chondrocyte activity. This leads to premature cellular apoptosis, suppressed cellular proliferation, growth plate arrest, and uncoupled bone remodeling in sublesional bone with unopposed osteoclastic resorption.

Osteocytic signalling pathways as therapeutic targets for bone fragility

“…This is associated with high prevalence of osteocyte apoptosis in mice and rats in vivo . 96, 97 Conversely, increasing levels of loading within the physiological range reduce the density of apoptotic osteocytes in rat ulnae. 98 …”

Apoptotic Osteocytes and the Control of Targeted Bone Resorption

“…Lack of mechanical stimulation [8,9] and excessive loading [10,24] both increase the prevalence of osteocyte apoptosis in mice and rats. The lack of mechanical forces could decrease survival signals induced by normal physical activity.…”

“…The accumulation of dead osteocytes in older individuals was reproduced more recently in mice, by measuring the prevalence of apoptotic TUNEL positive osteocytes [4]. In addition, increased osteocyte apoptosis was found in the absence of sex steroids [5,6], with glucocorticoid excess [7], due to immobilization [8,9], or induced by fatigue loading [10]. Conversely, agents that preserve bone mass and strength reduce the prevalence of osteocyte apoptosis.…”

Translational Research in Neurotrauma: Novel Mechanisms and Emerging Therapies

“…We and society as a whole expect great things from them, and their work is bound to help translate treatments to the clinic. We do want to highlight three articles, by Ng et al [1], by Morse [2], and by Xiong et al [3], which contain original data, evidence of these Investigators' progress, and these papers make this issue even more special.…”

“…Two papers deal with this issue, i.e., MRI imaging of vascular changes (Dijkhuizen) [9] and blood biomarkers (Zhang et al) [10]. The SCI papers also describe varied pathology and therapeutic approaches, including the role of vascular pathology (Benton and Hagg [11], Ng et al [1]), a comparison of pathophysiology between injuries induced by sPLA 2 versus by a contusion (Liu et al) [12], CSF biomarkers (Ng et al) [1], respiratory dysfunction (Terson de Paleville et al) [13], and cellular degenerative changes in the vertebral bone (Morse) [2]. Finally, a method which will enable analysis of many different components and outcome measurements across different neurotrauma studies is presented and will help to identify common pathological mechanisms that can be targeted for therapy (Ferguson et al) [14].…”