The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitro

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.

JUNB‐FBXO21‐ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy

“…The aging model was divided into four groups according to age ( n = 6 per group): 1 month old (1 M), 6 months old (6 M), 12 months old (12 M), and 18 months old (18 M). The MIA model (induced by the injection of 40 µl saline with or without 0.2 mg MIA into the intra‐articular cavity of 8‐week‐old SD rats after anesthetization with isoflurane as previously described) (Lu et al, 2020; Udo et al, 2016; H. Zhang et al, 2019) was also divided into four groups ( n = 6 per group) according to MIA treatment time: saline control (Ctrl), MIA treatment for 1 week (1 W), MIA treatment for 2 weeks (2 W), and MIA treatment for 3 weeks (3 W).…”

<p>High Glucose Downregulates Connexin 43 Expression and Its Gap Junction and Hemichannel Function in Osteocyte-like MLO-Y4 Cells Through Activation of the p38MAPK/ERK Signal Pathway</p>

“…Immunohistochemistry was performed as described previously. 24 Samples were sliced into 3-μm sections that were deparaffinized in xylene and an alcohol gradient, then washed using cold PBS. Enzymatic antigen retrieval (AR0026, Bosterbio, Pleasanton, CA, USA) was performed at 37°C for 30 min.…”

The Role of HDACs and HDACi in Cartilage and Osteoarthritis

“…HDAC3 is involved in the repression of cartilage matrix metabolism (Zhang et al, 2019b). MiR-193b-3p targets the 3 -UTR of HDAC3 and inhibits its expression.…”

“…These events are essential for regulating chondrocyte hypertrophy and the promotion of matrix gene expression ( Bradley et al, 2013 ). In the pathogenesis of OA, HDAC3 promotes OA progression via the regulation of the nuclear transportation of NF-κB in OA cartilage and chondrocytes with elevated MMP13 and ADAMTS5 expression ( Zhang et al, 2019b ). The contradictory phenomenon may be explained by the following: (1) HDAC3 is only essential for chondrocytes during the embryonic growth period; (2) HDAC3-deletion may slightly elevate inflammatory cytokines compared to normal chondrocytes, but significantly inhibit inflammation compared to chondrocytes treated with IL-1β.…”