Singh Nihal, Bhattacharjee Arijit, Kumar Praganesh, Katti Dhirendra S
Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh 208016, India; The Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh 208016, India.
Ganesh Shankar Vidyarthi Memorial Medical College, Kanpur 208002, Uttar Pradesh, India.
Life Sci. 2023 Dec 1;334:122212. doi: 10.1016/j.lfs.2023.122212. Epub 2023 Oct 27.
Osteoarthritis (OA), is a debilitating disease characterized by progressive cartilage degradation, synovial inflammation, and chondrocyte senescence. Various treatment agents independently targeting these hallmarks have been investigated. However, due to the complex multifaceted nature of OA, no disease-modifying osteoarthritis drugs are clinically available. In an attempt to overcome this, we developed a combinatorial approach and demonstrated the efficacy of TsC [Tissue inhibitor of metalloproteinase-3 (TIMP3) + sulfated carboxymethylcellulose (sCMC)] and piperlongumine (PL) combination for the amelioration of OA in a goat ex vivo OA model.
The efficacy of the drug combination was evaluated using the goat ex vivo OA explant model and results were validated in clinically relevant human OA cartilage explants. The chondroprotective effects were evaluated in terms of reduced inflammation and cartilage matrix loss, reduction in chondrosenescence, and reduced oxidative stress.
A combination of TsC and PL (TsC-PL) significantly reduced inflammation, cartilage matrix loss, chondrosenescence, and oxidative stress in the goat ex vivo OA model and showed chondroprotective effects. Further, similar chondroprotective effects were observed in human OA cartilage. Additionally, the coefficient of drug interaction analysis indicated that the combination of TsC and PL had a synergistic effect in reducing matrix degrading proteases and inflammation (goat ex vivo OA model) and Reactive oxygen species (ROS) production (human OA cartilage).
Combinatorial treatment with TsC and PL demonstrated potential disease-modifying effects for the treatment of osteoarthritis via inhibition of inflammation and senescence and supports the usage of treatment strategies targeting multiple pathological factors of OA simultaneously.
骨关节炎（OA）是一种使人衰弱的疾病，其特征为进行性软骨降解、滑膜炎症和软骨细胞衰老。针对这些特征的各种治疗药物已被研究。然而，由于OA具有复杂的多方面性质，临床上尚无改善病情的骨关节炎药物。为了克服这一问题，我们开发了一种联合治疗方法，并在山羊离体OA模型中证明了金属蛋白酶组织抑制剂-3（TIMP3）+硫酸化羧甲基纤维素（sCMC）（TsC）与荜茇酰胺（PL）联合使用对OA的改善作用。
使用山羊离体OA外植体模型评估药物组合的疗效，并在临床相关的人OA软骨外植体中验证结果。从减轻炎症和软骨基质损失、减少软骨衰老以及降低氧化应激方面评估软骨保护作用。
在山羊离体OA模型中，TsC与PL的组合（TsC-PL）显著减轻炎症、软骨基质损失、软骨衰老和氧化应激，并显示出软骨保护作用。此外，在人OA软骨中也观察到了类似的软骨保护作用。此外，药物相互作用系数分析表明，TsC与PL的组合在降低基质降解蛋白酶和炎症（山羊离体OA模型）以及活性氧（ROS）产生（人OA软骨）方面具有协同作用。
TsC与PL的联合治疗通过抑制炎症和衰老显示出对骨关节炎治疗的潜在改善病情作用，并支持同时针对OA多种病理因素的治疗策略的应用。
