Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing 100044, China.
Arthritis Institute, Peking University, Beijing 100044, China.
Molecules. 2022 Aug 31;27(17):5619. doi: 10.3390/molecules27175619.
High molecular weight hyaluronic acids (HMW-HAs) have been used for the palliative treatment of osteoarthritis (OA) for decades, but the pharmacological activity of HA fragments has not been fully explored due to the limited availability of structurally defined HA fragments. In this study, we synthesized a series glycosides of oligosaccharides of HA (o-HAs), hereinafter collectively referred to as o-HA derivatives. Their effects on OA progression were examined in a chondrocyte inflammatory model established by the lipopolysaccharide (LPS)-challenged ATDC5 cells. Cell Counting Kit-8 (CCK-8) assays and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed that o-HA derivatives (≤100 μg/mL) exhibited no cytotoxicity and pro-inflammatory effects. We found that the o-HA and o-HA derivatives alleviated LPS-induced inflammation, apoptosis, autophagy and proliferation-inhibition of ATDC5 cells, similar to the activities of HMW-HAs. Moreover, Western blot analysis showed that different HA derivatives selectively reversed the effects of LPS on the expression of extracellular matrix (ECM)-related proteins (MMP13, COL2A1 and Aggrecan) in ATDC5 cells. Our study suggested that o-HA derivatives may alleviate LPS-induced chondrocyte injury by reducing the inflammatory response, maintaining cell proliferation, inhibiting apoptosis and autophagy, and decreasing ECM degradation, supporting a potential oligosaccharides-mediated therapy for OA.
高分子量透明质酸（HMW-HA）已被用于缓解骨关节炎（OA）数十年，但由于结构定义明确的 HA 片段的有限可用性，HA 片段的药理学活性尚未得到充分探索。在这项研究中，我们合成了一系列透明质酸（HA）寡糖的糖苷（o-HA），以下统称为 o-HA 衍生物。在脂多糖（LPS）刺激的 ATDC5 细胞建立的软骨细胞炎症模型中，研究了它们对 OA 进展的影响。细胞计数试剂盒-8（CCK-8）测定和逆转录定量聚合酶链反应（RT-qPCR）表明，o-HA 衍生物（≤100μg/ml）无细胞毒性和促炎作用。我们发现，o-HA 和 o-HA 衍生物减轻了 LPS 诱导的 ATDC5 细胞炎症、凋亡、自噬和增殖抑制，与 HMW-HA 的活性相似。此外，Western blot 分析表明，不同的 HA 衍生物选择性地逆转了 LPS 对 ATDC5 细胞细胞外基质（ECM）相关蛋白（MMP13、COL2A1 和 Aggrecan）表达的影响。我们的研究表明，o-HA 衍生物可能通过减轻炎症反应、维持细胞增殖、抑制细胞凋亡和自噬以及减少 ECM 降解来减轻 LPS 诱导的软骨细胞损伤，为 OA 的潜在寡糖介导治疗提供了支持。
