Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation

  • Brain Behav Immun. 2022 May;102:53-70. doi: 10.1016/j.bbi.2022.02.015.
Jia Sun  1 ,  Fan-He Song  1 ,  Jia-Yi Wu  1 ,  Long-Qing Zhang  1 ,  Dan-Yang Li  1 ,  Shao-Jie Gao  1 ,  Dai-Qiang Liu  1 ,  Ya-Qun Zhou  2 ,  Wei Mei  3
Affiliations
  • 1. Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 3. Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
PMID: 35151829 DOI: 10.1016/j.bbi.2022.02.015
Abstract

Background: Our previous study indicated that Reactive Oxygen Species (ROS) are critically involved in chronic pain. Sestrin2 (Sesn2), a novel stress-inducible protein, is evidenced to reduce the generation of ROS. The study examined the role of Sesn2 in osteoarthritis (OA) pain and delineated the underlying molecular mechanisms.

Methods: In the present study, we investigated the impact of Sesn2 on mitochondrial biogenesis in a rat model of OA pain. After adeno-associated viral (AAV)-Sesn2EGFP was injected for 14 days, OA was induced by intra-articular injection of monosodium iodoacetate (MIA). We assessed pain behaviors (weight-bearing asymmetry and paw withdrawal threshold) and explored possible mechanisms in the L4-6 spinal cord.

Results: Our results showed that overexpression of Sesn2 in the spinal cord alleviated pain behaviors in OA rats. Moreover, overexpression of Sesn2 increased the activity of AMP-activated protein kinase (AMPK) signaling and significantly restored mitochondrial biogenesis. Besides, Sesn2 overexpression inhibited the activation of astrocytes and microglia, and decreased the production of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the spinal cord of the OA pain rats. These effects were significantly reversed by an AMPK Inhibitor.

Conclusions: Collectively, these results suggest that Sesn2 overexpression ameliorates mechanical allodynia and weight-bearing asymmetry in OA rats via activation of AMPK/PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Moreover, Sesn2 overexpression attenuates OA-induced neuroinflammation at least partly by activating AMPK signaling. Sesn2 may become an encouraging therapeutic strategy for OA pain relief and Other disorders.

Keywords
AMPK; Mitochondrial biogenesis; Neuroinflammation; Osteoarthritis pain; Sestrin2.
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