Department of Orthopedics, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550000, China; The Lab of Tissue Engineering and Translational Medicine, College of Medicine, Guizhou University, Guiyang, Guizhou 550000, China.
Department of Orthopedics, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550000, China; The Lab of Tissue Engineering and Translational Medicine, College of Medicine, Guizhou University, Guiyang, Guizhou 550000, China; Graduate School, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550025, China.
Acta Biomater. 2024 Nov;189:130-142. doi: 10.1016/j.actbio.2024.09.034. Epub 2024 Sep 23.
Osteoarthritis (OA) is a prevalent chronic degenerative disease affecting millions worldwide, with current treatment measures lacking efficacy in slowing disease progression. The synovial lymphatic system (SLS) has emerged as a crucial player in OA pathogenesis, with compromised drainage function contributing to disease advancement. Lymphatic endothelial cells (LECs) within the SLS are influenced by synovial macrophages, whose precise impact on LEC function remains unclear. Exosomes released by macrophages may serve as mediators of this interaction, with potential implications for OA progression. Here, we propose that polarized macrophages modulate LEC activity via exosome release in synovial tissue, with M2 macrophage-derived exosomes (M2) promoting LEC proliferation, migration, and lymphangiogenesis, potentially offering a therapeutic avenue for OA. Moreover, we developed an injectable thermosensitive hydrogel with the characteristic of sustained release of M2 for alleviating OA. The hydrogel was prepared by dynamically linking hyaluronic acid (HA) and Pluronic F-127 and loading M2, termed as M2 loaded HP hydrogel. The in vitro and in vivo experiments showed that M2 loaded HP hydrogel exhibits a controlled release profile of exosomes, thereby efficaciously fostering synovial lymphangiogenesis and enhancing synovial lymphatic drainage functionality under OA conditions, thus alleviating OA progression, and providing promising insights into OA therapeutic strategies. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a widespread degenerative disease with limited effective treatments to halt its progression. This research highlights the critical role of the synovial lymphatic system (SLS) in OA, focusing on how macrophage-derived exosomes influence lymphatic endothelial cell (LEC) function. We propose that M2 macrophage-derived exosomes (M2) enhance LEC activity, promoting lymphangiogenesis, and offering a therapeutic approach for OA. Furthermore, we developed an injectable thermosensitive hydrogel (M2 loaded HP hydrogel) for sustained M2 release. Our in vitro and in vivo experiments demonstrate that this hydrogel supports synovial lymphangiogenesis and improves lymphatic drainage, effectively alleviating OA progression. This study presents significant advancements in OA therapy, offering new insights into its management.
骨关节炎（OA）是一种普遍存在的慢性退行性疾病，影响着全球数以百万计的人，目前的治疗措施在减缓疾病进展方面效果不佳。滑膜淋巴系统（SLS）已成为 OA 发病机制中的关键因素，其引流功能受损导致疾病进展。SLS 中的淋巴内皮细胞（LEC）受滑膜巨噬细胞的影响，但其对 LEC 功能的确切影响尚不清楚。巨噬细胞释放的外泌体可能是这种相互作用的介质，这可能对 OA 的进展有影响。在这里，我们提出极化的巨噬细胞通过滑膜组织中外泌体的释放来调节 LEC 的活性，M2 巨噬细胞衍生的外泌体（M2）促进 LEC 的增殖、迁移和淋巴管生成，为 OA 提供了一种潜在的治疗途径。此外，我们开发了一种可注射的温敏水凝胶，具有持续释放 M2 的特性，用于缓解 OA。该水凝胶是通过动态连接透明质酸（HA）和 Pluronic F-127 并加载 M2 制备的，称为负载 M2 的 HP 水凝胶。体外和体内实验表明，负载 M2 的 HP 水凝胶具有外泌体的控制释放特性，从而有效地促进滑膜淋巴管生成，并在 OA 条件下增强滑膜淋巴引流功能，从而缓解 OA 的进展，为 OA 的治疗策略提供了有前途的见解。意义声明：骨关节炎（OA）是一种广泛存在的退行性疾病，目前有效的治疗方法有限，无法阻止其进展。这项研究强调了滑膜淋巴系统（SLS）在 OA 中的关键作用，重点研究了巨噬细胞衍生的外泌体如何影响淋巴内皮细胞（LEC）的功能。我们提出，M2 巨噬细胞衍生的外泌体（M2）增强 LEC 活性，促进淋巴管生成，并为 OA 提供一种治疗方法。此外，我们开发了一种可注射的温敏水凝胶（负载 M2 的 HP 水凝胶），用于持续释放 M2。我们的体外和体内实验表明，这种水凝胶支持滑膜淋巴管生成并改善淋巴引流，有效缓解 OA 进展。这项研究在 OA 治疗方面取得了重大进展，为其管理提供了新的见解。
