Chondroprotective Effects of a Histone Deacetylase Inhibitor, Panobinostat, on Pain Behavior and Cartilage Degradation in Anterior Cruciate Ligament Transection-Induced Experimental Osteoarthritic Rats

Abstract

Osteoarthritis (OA) is the most common articular degenerative disease characterized by chronic pain, joint inflammation, and movement limitations, which are significantly influenced by aberrant epigenetic modifications of numerous OA-susceptible genes. Recent studies revealed that both the abnormal activation and differential expression of histone deacetylases (HDACs) might contribute to OA pathogenesis. In this study, we investigated the chondroprotective effects of a marine-derived HDAC inhibitor, panobinostat, on anterior cruciate ligament transection (ACLT)-induced experimental OA rats. The intra-articular administration of 2 or 10 µg of panobinostat (each group, n = 7) per week from the 6th to 17th week attenuates ACLT-induced nociceptive behaviors, including secondary mechanical allodynia and weight-bearing distribution. Histopathological and microcomputed tomography analysis showed that panobinostat significantly prevents cartilage degeneration after ACLT. Moreover, intra-articular panobinostat exerts hypertrophic effects in the chondrocytes of articular cartilage by regulating the protein expressions of HDAC4, HDAC6, HDAC7, runt-domain transcription factor-2, and matrix metalloproteinase-13. The study indicated that HDACs might have different modulations on the chondrocyte phenotype in the early stages of OA development. These results provide new evidence that panobinostat may be a potential therapeutic drug for OA.

Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury-induced neuropathy in rats

“…It is an inhibitor of all types of HDACs with an IC50 in the nanomolar range (24). Our previous paper illustrated that panobinostat can ameliorate OA-induced nociception and decrease OA progression by mediating HDAC4, HDAC6, and HDAC7 in the cartilage of anterior cruciate ligament transection rats (27). Recently, other than our previous study, there are no investigations of panobinostat in pain treatment or for NP, which requires further research.…”

“…Panobinostat, a nonselective HDACi, is an FDA and EMA-approved drug for cancer treatment (24,25, 26). We previously reported that intra-articular administration of panobinostat attenuated nociception by inhibiting osteoarthritic (OA) progression in rats (27). However, the central nervous system (CNS) effects of panobinostat in nociception and NP remain unclear.…”

Intra-Articular Lactate Dehydrogenase A Inhibitor Oxamate Reduces Experimental Osteoarthritis and Nociception in Rats via Possible Alteration of Glycolysis-Related Protein Expression in Cartilage Tissue

“…Although subchondral bone structure remodeling was not a primary objective of our present study, a previous study indicated that the subchondral bone structure in joint regions is a characteristic feature of OA histopathology and participates in load-bearing pressures on the body after cartilage degeneration [ 51 ]. Our previous study found that the bone surface and the trabecular number of subchondral bone were significantly higher and lower in the ACLT-knee joint, respectively [ 52 ]. The advantages of high-resolution and three-dimensional (3D) reconstruction in micro-computed tomography (CT) have been widely applied in the evaluation of animal and human OA histopathology of subchondral bone areas [ 53 ].…”

Epigenetics in Knee Osteoarthritis: A 2020–2023 Update Systematic Review

“…These findings offer compelling evidence that Panobinostat holds promise as a potential therapeutic agent for OA. The increased expression of HDACs also modulated miR-146a, a negative controller of inflammation response in KOA [60].…”