Abstract
Spinal Cord Injury (SCI) is a debilitating condition characterized by damage to the spinal cord, resulting in loss of function, mobility, and sensation. Although increasingly prevalent in the US, no FDA-approved therapy exists due to the unfortunate complexity of the condition, and the difficulties of SCI may be furthered by the development of SCI-related complications, such as osteoporosis. SCI demonstrates two crucial stages for consideration: the primary stage and the secondary stage. While the primary stage is suggested to be immediate and irreversible, the secondary stage is proposed as a promising window of opportunity for therapeutic intervention. Enolase, a metabolic enzyme upregulated after SCI, performs non-glycolytic functions, promoting inflammatory events via extracellular degradative actions and increased production of inflammatory cytokines and chemokines. Neuron-specific enolase (NSE) serves as a biomarker of functional damage to neurons following SCI, and the inhibition of NSE has been demonstrated to reduce signs of secondary injury of SCI and to ameliorate dysfunction. This Viewpoint article involves enolase activation in the regulation of RANK-RANKL pathway and summarizes succinctly the mechanisms influencing osteoclast-mediated resorption of bone in SCI. Our laboratory proposes that inhibition of enolase activation may reduce SCI-induced inflammatory response and decrease osteoclast activity, limiting the chances of skeletal tissue loss in SCI.
Highlights
Spinal cord injury (SCI) is a condition in which trauma occurs to the spinal cord, resulting in compromised sensation, function, and mobility (Guilcher et al, 2019)
SCI-associated inflammation influences the development of chronic ischemic hypoxia, upregulation of Calpain proteases, activation of inflammatory signaling proteins, degeneration of the blood brain barrier, and production of reactive oxygen species (Cox et al, 2015; Shams et al, 2021)
In the US, 17,730 new SCI cases are reported annually, and this devastating condition has no FDA-approved therapy and no cure (Alabama, 2019). This secondary phase is suggested to be reversible, posing it as a promising window of opportunity for therapeutic intervention (Polcyn et al, 2017; Shams et al, 2021). This short review aims to summarize our viewpoints on the mechanisms influencing osteoporosis or skeletal tissue loss in SCI via enolase-mediated inflammation and promotion of the receptor activator of nuclear factor-κB (RANK) pathway, a modulator for osteoclastogenesis and bone resorption
Summary
Spinal cord injury (SCI) is a condition in which trauma occurs to the spinal cord, resulting in compromised sensation, function, and mobility (Guilcher et al, 2019). This secondary phase is suggested to be reversible, posing it as a promising window of opportunity for therapeutic intervention (Polcyn et al, 2017; Shams et al, 2021) This short review aims to summarize our viewpoints on the mechanisms influencing osteoporosis or skeletal tissue loss in SCI via enolase-mediated inflammation and promotion of the receptor activator of nuclear factor-κB (RANK) pathway, a modulator for osteoclastogenesis and bone resorption. LPS-stimulated Raw264.7 cells, a cellular model of osteoclast activity, demonstrate up-regulated RANKL expression. With enolase inhibition, osteoclast activation via RANKL binding can be perturbed following SCI, thereby preventing the recruitment of TRAF-6 and activation of JNK, p38, ERK, Akt and NF-κB (Fig. 2). Inhibition of enolase activation could mitigate SCI-induced osteoporosis or skeletal loss
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