Glycine N-acyltransferase deficiency in sensory neurons suppresses osteoarthritis pain.

Osteoarthritis (OA) is a degenerative joint disease characterized by chronic pain, which profoundly impacts patients' quality of life. The analgesic treatment for OA is an urgent clinical problem to be addressed. Glycine N-acyltransferase (GLYAT) is an enzyme that plays a vital role in facilitating biochemical reactions through the catalysis of glycine conjugation. Here, this study constructed an OA pain model using sodium monoiodoacetate (MIA) and discovered a significant upregulation of GLYAT in the dorsal root ganglia (DRG) of OA mice through transcriptomic sequencing. This study demonstrates GLYAT is predominantly expressed in DRG neurons and co-localizes with CGRP, IB4, or NF200-positive neurons. Overexpression of GLYAT leads to the development of prominent mechanical and thermal hyperalgesia. Loss of GLYAT effectively alleviates pain-like behaviors in OA mice without impairing baseline nociception and tactile sensations. Subsequent investigations show that GLYAT overexpression disrupts the redox balance and increases reactive oxygen species (ROS) levels within DRG neurons, leading to the upregulation of transient receptor potential vanilloid 1 (TRPV1) channel. Furthermore, ROS clearance or TRPV1 blockade in GLYAT-overexpressing mice significantly increased mechanical withdrawal threshold and thermal withdrawal latency. Collectively, these results demonstrate that GLYAT regulates OA pain by increasing ROS production and TRPV1 channel expression. This work also suggests the potential of GLYAT as a novel target for analgesic therapies. PERSPECTIVE: This article highlights the innovative finding of increased GLYAT levels in DRG neurons of the mice with OA pain. The role of GLYAT in regulating ROS and TRPV1 levels suggests its potential as a target for managing OA pain.