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. 2023 Dec;31(12):1567-1580.
doi: 10.1016/j.joca.2023.07.008. Epub 2023 Aug 6.

TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain

Eui Ho Park  1 , Jinwon Seo  2 , Yunsin Lee  2 , Kiwon Park  2 , Kyung-Ran Kim  2 , Sujeong Kim  2 , Ali Mobasheri  3 , Heonsik Choi  4
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Free article

TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain

Eui Ho Park et al. Osteoarthritis Cartilage. 2023 Dec.
Free article

Abstract

Objective: TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-β1 (TGF-β1), has been developed as a novel cell-based gene therapy and a candidate for disease modifying osteoarthritis drug (DMOAD). We aim to investigate analgesic mechanism of TG-C in a pre-clinical animal model with monoiodoacetate (MIA)-induced pain.

Design: We used a rat MIA model of osteoarthritis (OA) pain. We examined that TG-C can regulate pain by inhibiting the upregulation of various pain mediators in both knee joint tissue and dorsal root ganglia (DRG) (n = 112) and alleviating pain behavior (n = 41) and neuronal hyperexcitability in DRG (n = 60), afferent nerve fiber (n = 24), and spinal cord (n = 35).

Results: TG-C significantly alleviated pain-related behavior by restoring altered dynamic weight bearing and reduced mechanical threshold of the affected hindlimb. TG-C significantly suppressed the expression of nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) in inflamed joint tissue. TG-C significantly suppressed the upregulation of tropomyosin receptor kinase A (TrkA) and nerve injury/regeneration protein (GAP43) and activation of Iba1-positive microglial cells in DRG. TG-C significantly recovered neuronal hyperexcitability by restoring RMP and firing threshold and frequency of DRG neurons, attenuating firing rates of mechanosensitive C- or Aδ-nerve fiber innervating knee joint, and lowering increased miniature and evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) in the spinal cord.

Conclusion: Our results demonstrated that TG-C exerted potent analgesic effects in a rat MIA model of OA pain by inhibiting the upregulation of pain mediators and modulating neuronal sensitization.

Keywords: Analgesia; Mechanosensitive C- or Aδ-nerve fiber; Monoiodoacetate (MIA); Osteoarthritis (OA); Pain mediator; TissueGene-C (TG-C).

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Conflict of interest statement

Declaration of Competing Interest The authors except Eui Ho Park and Ali Mobasheri are current or past employees of Kolon Life Science, Inc. developing TissueGene-C. This does not alter our adherence to all journal’s policies on sharing data and materials. Eui Ho Park and Ali Mobasheri declare no financial conflict of interest.

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