Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Molecules. 2021 Nov 19;26(22):6993. doi: 10.3390/molecules26226993.
Osteoarthritis (OA) is a complex disease characterized by structural, functional, and metabolic deteriorations of the whole joint and periarticular tissues. In the current study, we aimed to investigate the possible effects of tempol on knee OA induced by the chemical chondrotoxic monosodium iodoacetate (MIA) which closely mimics both the pain and structural changes associated with human OA. Rats were administrated oral tempol (100 mg/kg) one week post-MIA injection (3 mg/50 μL saline) at the right knee joints for 21 consecutive days. Tempol improved motor performance and debilitated the MIA-related radiological and histological alterations. Moreover, it subsided the knee joint swelling. Tempol decreased the cartilage degradation-related biomarkers as matrix metalloproteinase-13, bone alkaline phosphatase (bone ALP), and fibulin-3. The superoxide dismutase mimetic effect of tempol was accompanied by decreased NADPH oxidase 4 (NOX4), inflammatory mediators, nuclear factor-kappa B (NF-κB), over-released transforming growth factor-β1 (TGF-β1). Tempol decreased the expression of chemokine (C-C motif) ligand 2 (CCL2). On the molecular level, tempol reduced the phosphorylated protein levels of p38 mitogen-activated protein kinase (MAPK), and small mother against decapentaplegic 3 homologs (SMAD3). These findings suggest the promising role of tempol in ameliorating MIA-induced knee OA in rats via collateral suppression of the catabolic signaling cascades including TGF-β1/SMAD3/NOX4, and NOX4/p38MAPK/NF-κB and therefore modulation of oxidative stress, catabolic inflammatory cascades, chondrocyte metabolic homeostasis.
骨关节炎（OA）是一种复杂的疾病，其特征是整个关节和关节周围组织的结构、功能和代谢恶化。在目前的研究中，我们旨在研究 Tempo 在化学性软骨毒性单碘乙酸盐（MIA）诱导的膝骨关节炎中的可能作用，该物质可模拟与人类 OA 相关的疼痛和结构变化。在右侧膝关节注射 MIA（3mg/50μL 生理盐水）后一周，给大鼠口服 Tempo（100mg/kg），连续 21 天。Tempo 改善了运动表现，并减弱了与 MIA 相关的放射学和组织学改变。此外， Tempo 减轻了膝关节肿胀。Tempo 降低了与软骨降解相关的生物标志物，如基质金属蛋白酶-13、骨碱性磷酸酶（骨 ALP）和纤维蛋白 3。Tempo 的超氧化物歧化酶模拟作用伴随着 NADPH 氧化酶 4（NOX4）、炎症介质、核因子-κB（NF-κB）、过度释放的转化生长因子-β1（TGF-β1）的减少。Tempo 降低了趋化因子（C-C 基序）配体 2（CCL2）的表达。在分子水平上，Tempo 降低了磷酸化 p38 丝裂原激活蛋白激酶（MAPK）和小母亲对抗 decapentaplegic 3 同源物（SMAD3）的蛋白水平。这些发现表明 Tempo 通过协同抑制包括 TGF-β1/SMAD3/NOX4、NOX4/p38MAPK/NF-κB 在内的分解代谢信号通路，以及调节氧化应激、分解代谢炎症级联、软骨细胞代谢稳态，在改善大鼠 MIA 诱导的膝骨关节炎中具有广阔的应用前景。
