背景:骨关节炎(OA)是一种与衰老相关的退行性关节疾病,其特征是关节不适和僵硬。衰老软骨细胞释放促炎细胞因子和细胞外基质降解蛋白,创造一个炎症微环境,阻碍软骨形成和加速基质降解。靶向衰老软骨细胞可能是治疗OA的一种有希望的方法。在这里,我们描述了一种可注射肽-水凝胶的工程,该肽-水凝胶缀合了干细胞归巢肽PFSSTKT,用于携带载有质粒DNA的纳米颗粒和TanshinonIIA(pPNPTIIA@PFS),旨在通过改善衰老的微环境和促进软骨再生来减轻OA的进展。
结果:具体来说,pPNP+TIIA@PFS提高抗衰老蛋白Klotho的浓度,并阻断衰老信号向相邻健康软骨细胞的传递,显着减轻软骨细胞衰老和增强软骨完整性。此外,pPNP+TIIA@PFS募集骨髓间充质干细胞并指导其随后分化为软骨细胞,实现令人满意的软骨形成。在手术诱导的OA模型大鼠中,pPNP+TIIA@PFS的应用导致骨赘形成减少和关节软骨退变的减轻。
结论:总体而言,这项研究介绍了一种新的方法来缓解OA的进展,为OA治疗中潜在的临床翻译奠定了基础。
BACKGROUND: Osteoarthritis (OA) is an aging-related degenerative joint disorder marked by joint discomfort and rigidity. Senescent chondrocytes release pro-inflammatory cytokines and extracellular matrix-degrading proteins, creating an inflammatory microenvironment that hinders chondrogenesis and accelerates matrix degradation. Targeting of senescent chondrocytes may be a promising approach for the treatment of OA. Herein, we describe the engineering of an injectable peptide-hydrogel conjugating a stem cell-homing peptide PFSSTKT for carrying plasmid DNA-laden nanoparticles and Tanshinon IIA (pPNP + TIIA@PFS) that was designed to attenuate OA progression by improving the senescent microenvironment and fostering cartilage regeneration.
RESULTS: Specifically, pPNP + TIIA@PFS elevates the concentration of the anti-aging protein Klotho and blocks the transmission of senescence signals to adjacent healthy chondrocytes, significantly mitigating chondrocyte senescence and enhancing cartilage integrity. Additionally, pPNP + TIIA@PFS recruit bone mesenchymal stem cells and directs their subsequent differentiation into chondrocytes, achieving satisfactory chondrogenesis. In surgically induced OA model rats, the application of pPNP + TIIA@PFS results in reduced osteophyte formation and attenuation of articular cartilage degeneration.
CONCLUSIONS: Overall, this study introduces a novel approach for the alleviation of OA progression, offering a foundation for potential clinical translation in OA therapy.