Abstract
Spinal pain is a major clinical problem, however, its origins and underlying mechanisms remain unclear. Here we report that in mice, osteoclasts induce sensory innervation in the porous endplates which contributes to spinal hypersensitivity in mice. Sensory innervation of the porous areas of sclerotic endplates in mice was confirmed. Lumbar spine instability (LSI), or aging, induces spinal hypersensitivity in mice. In these conditions, we show that there are elevated levels of PGE2 which activate sensory nerves, leading to sodium influx through Nav 1.8 channels. We show that knockout of PGE2 receptor 4 in sensory nerves significantly reduces spinal hypersensitivity. Inhibition of osteoclast formation by knockout Rankl in the osteocytes significantly inhibits LSI-induced porosity of endplates, sensory innervation, and spinal hypersensitivity. Knockout of Netrin-1 in osteoclasts abrogates sensory innervation into porous endplates and spinal hypersensitivity. These findings suggest that osteoclast-initiated porosity of endplates and sensory innervation are potential therapeutic targets for spinal pain.
Highlights
The positive association between vertebral endplate signal changes (i.e., Modic changes) and LBP has been shown by magnetic resonance imaging (MRI) examination[13,14]
We recently reported that Prostaglandin E2 (PGE2), produced from arachidonic acid by the enzymatic activity of cyclooxygenase 2 (COX-2), during bone remodeling activates PGE2 receptor 4 (EP4) in CGRP+ sensory nerves to tune down sympathetic tones further inducing osteoblastic differentiation of MSCs30
The results revealed that each measure of spontaneous activity decreased significantly at 4 and 8 weeks after Lumbar spine instability (LSI) surgery relative to sham surgery (Fig. 1b–e)
Summary
The positive association between vertebral endplate signal changes (i.e., Modic changes) and LBP has been shown by magnetic resonance imaging (MRI) examination[13,14]. Since pain is produced by nociceptors, LBP may be caused by sensory innervation into endplates. Zoledronic acid and denosumab, drugs that inhibit osteoclast activities, have shown analgesic effects in patients with Modic changes associated LBP26,27, with the implication of a potential role of osteoclast activity in sensory nerve innervation. EP4 receptor is considered the primary mediator of PGE2-evoked inflammatory pain hypersensitivity and sensitization of sensory neurons[28,29]. PGE2 could modulate the TTX-R sodium current in DRG neurons and promote Nav1.8 trafficking to the cell surface[37,38]. The elevated PGE2 in porous endplates induces sodium influx into the cells to stimulate sensory nerves that leads to spinal pain. Inhibition of osteoclast activity attenuated sensory innervation in porous endplates and pain behavior
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