Abstract
Skeletal interoception regulates bone homeostasis through the prostaglandin E2 (PGE2) concentration in bone. Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging. We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain. Importantly, treatment with a high-dose cyclooxygenase 2 inhibitor (celecoxib, 80 mg·kg−1 per day) decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability. However, this treatment impaired bone formation in porous endplates, and spinal pain recurred after discontinuing the treatment. Interestingly, low-dose celecoxib (20 mg·kg−1 per day, which is equivalent to one-quarter of the clinical maximum dosage) induced a latent inhibition of spinal pain at 3 weeks post-treatment, which persisted even after discontinuing treatment. Furthermore, when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib, endplate porosity was reduced significantly, which was associated with decreased sensory nerve innervation and spinal pain. These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity, thereby reducing sensory innervation and spinal pain in mice.
Highlights
Low back pain (LBP) is a common disease leading to a decline in mobility and to frailty worldwide.[1,2] LBP is the leading cause of activity limitations and work absences, affecting 80% of people at some point during their lives.[3]
We have identified prostaglandin E2 (PGE2)/EP4-mediated skeletal interoception, in which PGE2 secreted by osteoblasts activates EP4 in sensory nerves to induce phosphorylation of cAMP-response element binding protein (CREB) in the hypothalamus as an upstream interoceptive signaling pathway, where sympathetic activity is decreased to promote osteoblastic bone formation as the downstream interoceptive action.[27]
Low-dose celecoxib reduced sensory innervation in porous endplates and transient receptor potential vanilloid 1 (TRPV1) expression in dorsal root ganglion (DRG) neurons To further investigate the neuronal mechanism by which reduced endplate porosity is associated with a decrease in spinal pain, we examined the effect of low-dose (20 mg·kg−1 per day) celecoxib on sensory innervations in porous vertebral endplates
Summary
Low back pain (LBP) is a common disease leading to a decline in mobility and to frailty worldwide.[1,2] LBP is the leading cause of activity limitations and work absences, affecting 80% of people at some point during their lives.[3]. NSAIDs comprise of the lumbar vertebral body in the mice with LSI (Supplementary types: nonselective NSAIDs (e.g., ibuprofen) that inhibit both Fig. 2A–E) All, these findings showed that low-dose cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) enzymes celecoxib treatment reduces endplate porosity and induces latent and selective NSAIDs (e.g., celecoxib) that inhibit only the COX-2 inhibition of LBP. We postulate that new bone formation in porous endplates they should be prescribed at the lowest effective dose for the may be promoted by a physiological concentration of PGE2 as a shortest duration.[46] COX-2 inhibitors are widely used for skeletal potential mechanism to reduce sensory innervation and spinal pain treatment, with annual sales totaling more than $7 billion in pain. High-dose celecoxib treatment, as shown by qRT-PCR and ELISAs, relative to low-dose, very low-dose and vehicle treatment
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