Zhang He, Ji Lu, Yang Yue, Wei Yingliang, Zhang Xiaoning, Gang Yi, Lu Jinghan, Bai Lunhao
Department of Orthopedic Surgery, Shengjing Hospital, China Medical University, Shenyang, China.
Department of Gynecology and Obstetrics, Shengjing Hospital, China Medical University, Shenyang, China.
Front Physiol. 2019 Aug 20;10:1060. doi: 10.3389/fphys.2019.01060. eCollection 2019.
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.
骨关节炎（OA）是一种以非细菌性炎症为特征的疾病。组蛋白去乙酰化酶3（HDAC3）是导致非OA炎症性疾病发生的炎症过程中的关键正向调节因子。然而，HDAC3在OA中的具体作用仍不清楚，运动疗法在OA中的潜在机制需要更多研究。我们研究了HDAC3在运动疗法治疗的OA中的作用。通过蛋白质免疫印迹法、逆转录聚合酶链反应（RT-PCR）和免疫组织化学法检测HDAC3、含血小板反应蛋白基序的解聚素和金属蛋白酶-5（ADAMTS-5）、基质金属蛋白酶-13（MMP-13）、HDAC3和核因子-κB（NF-κB）的表达水平。分别根据曼金评分和骨关节炎研究学会国际工作组（OARSI）评分，通过苏木精-伊红染色和甲苯胺蓝O染色来评估软骨损伤和OA。我们发现中等强度的跑步机运动可以缓解OA。同时，与OA组（OAG）或OA +高强度或低强度跑步机运动组（OAH或OAL）相比，OA +中等强度跑步机运动组（OAM）中HDAC3、MMP-13、ADAMTS-5和NF-κB的表达降低，而Ⅱ型胶原蛋白增加。此外，我们发现选择性HDAC3抑制剂RGFP966也可通过抑制NF-κB的核转位来减轻OA大鼠模型中的炎症。为了进一步探讨HDAC3与NF-κB之间的关系，我们研究了在RGFP966刺激下，白细胞介素-1β处理的软骨细胞中NF-κB重新定位的变化。我们发现RGFP966可通过调节HDAC3/NF-κB途径抑制OA炎症标志物的表达。这些研究表明，RGFP966因此是一种有前景的治疗OA的新药。
