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

Objective: TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-beta 1 (TGF-beta 1), 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 A delta-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.(c) 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).