Background/Purpose: Osteoarthritis is one of the leading causes of chronic pain and disability worldwide with 500 million people affected. We have previously reported that nociceptor-conditional Piezo2 knock-out mice (NaV1.8cre-Piezo2fl/fl; Piezo2cko), were protected from pain-related behaviors associated with a surgical model of OA along with spontaneous OA with aging, while joint damage was not affected. Persistent pain development is associated with molecular and cellular changes in the dorsal root ganglia (DRG), which contain the cell bodies of nociceptors as well as various types of non-neuronal cells. Previously, in wild-type mice, we have reported elevated levels of immune cells such as macrophages in the knee-innervating DRG in mouse models of OA, but the link between stimuli sensed by nociceptors in the knee joint and the recruitment of these cells in the DRG is not yet fully elucidated. The objective of the present study was to investigate whether the ion channel Piezo2, expressed by nociceptors, plays a role in these changes within the dorsal root ganglia in a mouse model of osteoarthritis (OA).

Methods: Twelve-week-old WT and Piezo2cko mice of both sexes underwent PMX or sham surgery (n=9-10). Mice were behaviorally assessed pre-operatively and every 4 weeks thereafter for knee hyperalgesia and weight bearing asymmetry. At 13 weeks post operatively knees were used for OA scoring by H&E and Safranin-O. Spinal cords were used for immunofluorescent staining for IBA1+ microglia and GFAP+ astrocytes. Separate cohorts of mice were used to perform flow cytometry or bulk RNAseq on L3-L5 DRG.

Results: Piezo2cko mice of both sexes were protected throughout the time course from knee hyperalgesia and from weight bearing asymmetry development, however Piezo2cko mice developed OA pathology at the same level as WT PMX mice. Piezo2cko PMX mice were protected from innate immune cell influx of NK1.1+ and F4/80+ cells compared to WT PMX mice, which was supported by DRG bulk RNAseq findings. Neuroimmune protection seen at the DRG extends to the CNS as Piezo2cko PMX mice had less activated IBA1+ microglia. In addition, male WT PMX mice displayed an increase in the number of GFAP+ astrocytes compared to Piezo2cko PMX mice. No differences in GFAP+ astrocytes were observed in female mice across the conditions.

Conclusion: Piezo2cko from nociceptors was protective against pain-related behaviors and neuroimmune changes associated with OA in the PMX model in both sexes. However, conditional knockout did not protect from OA joint pathology. Targeting Piezo2 could prove to be a valuable target for inhibiting chronic pain in patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-nociceptor-expressed-piezo2-in-nervous-system-immune-cell-infiltration-in-a-mouse-model-of-osteoarthritis/