TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain.
Osteoarthritis Cartilage
; 31(12): 1567-1580, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-37544583
ABSTRACT
OBJECTIVE:
TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-ß1 (TGF-ß1), 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoartrite
/
Dor
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Osteoarthritis Cartilage
Ano de publicação:
2023
Tipo de documento:
Article