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.
Highlights
Panobinostat (LBH589), a histone deacetylase (HDAC) inhibitor, was approved for patients with multiple myeloma and other hematological malignancies by the United StatesFood and Drug Administration (US-FDA) in 2015 [1]
Compared with the control group, changes in the hind paw weight distribution had increased significantly (64.7 ± 5.7 vs. 2.2 ± 1.1 g; p < 0.01; Figure 1A), and the paw withdrawal threshold had decreased significantly (1.2 ± 0.2 vs. 10.0 ± 0.0 g; p < 0.01; Figure 1B) at the 24th week after anterior cruciate ligament transection (ACLT). These results indicate that weight-bearing asymmetry and mechanical allodynia were produced with ALCT-induced OA progression
Sci. 2021, 22, x FOR PEER REVIEW and high-dose panobinostat treatment groups (Figure 5B,C). These results suggest that panobinostat administration significantly downregulates RUNX2 and MMP13 in cartilage tissues after ACLT
Summary
Panobinostat (LBH589), a histone deacetylase (HDAC) inhibitor, was approved for patients with multiple myeloma and other hematological malignancies by the United StatesFood and Drug Administration (US-FDA) in 2015 [1]. LBH589 was developed from a marine natural product, psammaplin A (PSA) [2,3,4], which was first isolated from a marine sponge Psammaplvsilla sp. PSA was discovered as an HDAC inhibitor for anticancer properties from p21, a cyclin-dependent kinase 2 promoter assay system [6,7]. Several interesting derivatives were developed, the pharmacological profile of PSA was not improved successfully [7,8]. Another natural compound, trichostatin A ( an HDAC inhibitor), was isolated using the same p21 promoter assay [7,8,9]. Structure modification was continued by computational docking studies to obtain LAQ824, which showed increased antiproliferative effects in several cancer cell lines (including A549 (lung), HCT166 (colon), and MDA435
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
