trichostatin-a and Osteoarthritis--Knee

To examine the ability of a broad-spectrum histone deacetylase (HDAC) inhibitor to protect cartilage in vivo, and to explore the effects of class-selective HDAC inhibitors and small interfering RNA (siRNA)-induced knockdown of HDACs on metalloproteinase expression and cartilage degradation in vitro.. A destabilization of the medial meniscus (DMM) model was used to assess the in vivo activity of the HDAC inhibitor trichostatin A (TSA). Human articular chondrocytes (HACs) and SW-1353 chondrosarcoma cells were treated with cytokines and TSA, valproic acid, MS-275, or siRNA, and quantitative reverse transcription-polymerase chain reaction was performed to determine the effect of treatment on metalloproteinase expression. HDAC inhibitor activity was detected by Western blotting. A bovine nasal cartilage (BNC) explant assay was performed to measure cartilage resorption in vitro.. Systemically administered TSA protected cartilage in the DMM model. TSA, valproic acid, and MS-275 repressed cytokine-induced MMP1 and MMP13 expression in HACs. Knockdown of each class I HDAC diminished interleukin-1-induced MMP13 expression. All of the HDAC inhibitors prevented degradation of BNC, in which TSA and MS-275 repressed cytokine-induced MMP expression.. Inhibition of class I HDACs (HDAC-1, HDAC-2, HDAC-3) by MS-275 or by specific depletion of HDACs is capable of repressing cytokine-induced metalloproteinase expression in cartilage cells and BNC explants, resulting in inhibition of cartilage resorption. These observations indicate that specific inhibition of class I HDACs is a possible therapeutic strategy in the arthritides.

Topics: Animals; Benzamides; Cattle; Cell Line, Tumor; Cells, Cultured; Chondrocytes; Disease Models, Animal; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Metalloproteases; Mice; Mice, Inbred C57BL; Nasal Cartilages; Osteoarthritis, Knee; Pyridines; RNA, Small Interfering; Tubulin

The aim of this study was to investigate the effects of trichostatin A (TSA) on expression of cathepsins in cartilage in experimental osteoarthritis (OA). OA was induced in 18 rabbits by bilateral anterior cruciate ligament transection (ACLT). Four weeks after surgery, rabbits received intra-articular injection with TSA dissolved in the dimethylsulphoxide (DMSO) in the right knees and DMSO in the left knees once a week for 5 weeks. Rabbits were killed 7 days after the last injection. The knee joints were assessed by morphological and histological examination. Messenger RNA expression of cathepsins K, B, L, S and cystatin C was studied by real-time PCR. TSA inhibited the expression of cathepsins K, B, L, S and cystatin C accompanied with the less degradation in cartilage. The results suggest that TSA exhibits protective effects against cartilage degradation in rabbits with OA and the effects may be associated with the inhibition of cathepsins.

Topics: Animals; Cathepsins; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Hydroxamic Acids; Male; Osteoarthritis, Knee; Protease Inhibitors; Rabbits

Recent studies suggest that histone deacetylase (HDAC) inhibitors may therapeutically prevent cartilage degradation in osteoarthritis (OA). Matrix metalloproteinase-13 (MMP-13) plays an important role in the pathogenesis of this disease and in the present study we investigated the correlation between HDACs and MMP-13. Comparing the expression of different HDACs in cartilage from OA patients and healthy donors, HDAC7 showed a significant elevation in cartilage from OA patients. High level of HDAC7 expression in OA cartilage was also confirmed by immunohistochemistry. Knockdown of HDAC7 by small interference RNA (siRNA) in SW1353 human chondrosarcoma cells strongly suppressed interleukin (IL)-1-dependent and independent induction of MMP-13 gene expression. In conclusion, elevated HDAC7 expression in human OA may contribute to cartilage degradation via promoting MMP-13 gene expression, suggesting the critical role of MMP-13 in OA pathogenesis.

Topics: Adult; Biomarkers; Cartilage, Articular; Cell Line, Tumor; Chondrocytes; Gene Expression Regulation, Enzymologic; Gene Knockdown Techniques; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Immunohistochemistry; Matrix Metalloproteinase 13; Middle Aged; Osteoarthritis, Knee; RNA, Small Interfering; Young Adult