acy-1215 and Osteoarthritis

Osteoarthritis (OA) is involved in these pathophysiological changes of articular cartilage, subchondral bone and synovium. As a selective HDAC6 inhibitor, Ricolinostat (ACY-1215) has demonstrated chondroprotective effects in OA. However, its efficacy remains unclear in subchondral bone. In this study, we found that the mRNA and protein levels of HDAC6 were elevated in human OA osteoblasts in vitro. PI3K/AKT signaling pathway was suppressed with downregulation of VEGF expression in osteoblasts after ACY-1215 treatment. ACY-1215 promoted apoptosis of OA osteoblast in a concentration-dependent manner, and the expression of apoptosis-related proteins was also changed by activating caspase pathway. Moreover, western blotting showed decreased expression of MMP9 and MMP13 in IL-1β-induced chondrocytes after co-culture with ACY-1215-stimulated osteoblasts. These data of immunohistochemistry and micro-CT from OA model mice also demonstrated the weak staining of MMPs in cartilage and prevention of aberrant subchondral bone formation after ACY-1215 injection. Therefore, high expression of HDAC6 in osteoblasts also contributed to the OA progression, and our study provided a new evidence that HDAC6 inhibitor may be a potential therapeutic drug for OA.

Topics: Aged; Animals; Apoptosis; Cartilage, Articular; Chondrocytes; Female; Humans; Hydroxamic Acids; Interleukin-1beta; Male; Matrix Metalloproteinase 13; Mice; Mice, Inbred C57BL; Osteoarthritis; Osteoblasts; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Signal Transduction; Vascular Endothelial Growth Factor A

Cartilage degeneration is a basic pathological feature of osteoarthritis (OA), and there is growing evidence that it is associated with inflammation. ACY-1215, a selective HDAC6 inhibitor, has been reported to have anti-inflammatory effects. Here, we investigated the anti-inflammatory and chondroprotective effects of ACY-1215 in IL-1β-stimulated human primary chondrocytes and C28/I2 cells. The results suggested that ACY-1215 can markedly suppress the expression of inflammatory factors, including IL-1β and IL-6 in human primary chondrocytes and C28/I2 cells. Furthermore, ACY-1215 exerts potent chondroprotection through the amelioration of cartilage degradation by inhibiting the expression of matrix-degrading proteases, including MMP-1 and MMP-13 in chondrocytes. These effects may be related to ACY-1215 induced down-regulation of NF-κB and STAT3 pathways in OA chondrocytes. Taken together, our results show that ACY-1215 may be a potential and promising therapeutic drug for the management of OA.

Topics: Anti-Inflammatory Agents; Cells, Cultured; Chondrocytes; Dose-Response Relationship, Drug; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; NF-kappa B; Osteoarthritis; Pyrimidines; Signal Transduction; STAT3 Transcription Factor