PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib

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.