Abstract
Osteoarthritis (OA) is a disease characterized by non-bacterial inflammation. Histone deacetylase 3 (HDAC3) is a crucial positive regulator in the inflammation that leads to the development of non-OA inflammatory disease. However, the precise involvement of HDAC3 in OA is still unknown, and the underlying mechanism of exercise therapy in OA requires more research. We investigated the involvement of HDAC3 in exercise therapy-treated OA. Expression levels of HDAC3, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), matrix metalloproteinase-13 (MMP-13), HDAC3 and nuclear factor-kappaB (NF-kappaB) were measured by western blotting, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Cartilage damage and OA evaluation were measured by hematoxylin and eosin staining and Toluidine blue O staining according to the Mankin score and OARSI score, respectively. We found that moderate-intensity treadmill exercise could relieve OA. Meanwhile, the expression of HDAC3, MMP-13, ADAMTS-5 and NF-kappaB decreased, and collagen II increased in the OA + moderate-intensity treadmill exercise group (OAM) compared with the OA group (OAG) or OA + high- or low-intensity treadmill exercise groups (OAH or OAL). Furthermore, we found the selective HDAC3 inhibitor RGFP966 could also alleviate inflammation in OA rat model through inhibition of nuclear translocation of NF-kappaB. To further explore the relationship between HDAC3 and NF-kappaB, we investigated the change of NF-kappaB relocation in IL-1β-treated chondrocytes under the stimulation of RGFP966. We found that RGFP966 could inhibit the expression of inflammatory markers of OA via regulation of HDAC3/NF-kappaB pathway. These investigations revealed that RGFP966 is therefore a promising new drug for treating OA.
Highlights
Osteoarthritis (OA) is a highly prevalent degenerative disease worldwide
We found that all rats in the OA + low-intensity of treadmill exercise group (OAL) group were able to complete the program; dropout began at 3 week, and 80% of rats completed the program in the OA + moderate-intensity of treadmill exercise group (OAM) group
We found that expression of histone deacetylase 3 (HDAC3) protein was significantly decreased in the OAM group compared to OA model group (OAG) (Figures 3A,B,E,G), and that the total HDAC3 protein was decreased in the OAM compared to OA + high-intensity of treadmill exercise group (OAH) group and OAG (Figures 4A,F)
Summary
Osteoarthritis (OA) is a highly prevalent degenerative disease worldwide. In 2015, almost 54.4 million adults were diagnosed with OA in the United States (Cheng et al, 2010); this number is increasing rapidly. OA is a multi-factor disease, and obesity, age, gender, and abnormal loading of joints are all able to stimulate production of inflammatory mediators secreted by chondrocyte and synovium including IL-1β, ADAMTS-5 and MMP-13, which contribute to OA characterized by cartilage erosion, subchondral bone formation, and joint swelling (Ashkavand et al, 2013; Berenbaum, 2013; Mobasheri and Batt, 2016). Exercise therapy has received considerable attention for treating OA, as an alternative to surgery (McAlindon et al, 2014). Improper exercise can aggravate OA (Franciozi et al, 2013). The mechanism of different intensities of exercise involved in the variable effect on OA is still unknown
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