Department of Pharmacology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea; Degenerative InterDiseases Research Center, Ajou University School of Medicine, Suwon, 16499, Republic of Korea; CIRNO, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
Department of Molecular Science & Technology, Ajou University, Suwon, 16499, Republic of Korea.
Biomaterials. 2021 Aug;275:120967. doi: 10.1016/j.biomaterials.2021.120967. Epub 2021 Jun 10.
Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. We report an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a potential therapeutic agent for OA treatment. In mouse primary articular chondrocytes, HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight HA, and the cellular uptake of HA-NPs increased by ectopic expression of CD44, using an adenoviral delivery system (Ad-Cd44). HA-NP showed in vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free high-molecular-weight (HMW) HA. CD44 expression increased in the damaged articular cartilage of patients and mice with OA. Ad-Cd44 infection and IL-1β treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both Cd44 deficiency and intra-articular injection of HA-NP protected joint cartilage against OA development in the OA mouse model. NF-κB was found to mediate CD44-induced catabolic factor expression and HA-NP inhibited CD44-induced NF-κB activation in chondrocytes. Our results identify an empty HA-NP as a potential therapeutic agent targeting CD44 for OA treatment, and the CD44-NF-κB-catabolic gene axis as an underlying mechanism of destructive cartilage disorders.
尽管骨关节炎（OA）是最常见的退行性关节疾病，但目前尚无有效的疾病修饰治疗方法。我们报告了一种空的自组装透明质酸纳米颗粒（HA-NP），它可以作为治疗 OA 的潜在治疗剂。在小鼠原代关节软骨细胞中，HA-NP 阻断了游离低分子量 HA 的受体介导的细胞摄取，并且通过腺病毒（Ad-Cd44）递送系统过表达 CD44 时，HA-NP 的细胞摄取增加。与游离高分子量（HMW）HA 相比，HA-NP 在体外对透明质酸酶的消化具有抗性，并且在体内膝关节中的保留能力更强。在 OA 患者和 OA 小鼠的受损关节软骨中，CD44 的表达增加。Ad-Cd44 感染和 IL-1β 处理通过增强原代关节软骨细胞中分解代谢基因的表达诱导体外 OA 表型，而 HA-NP 可减轻这些作用，但 HMW HA 则不能。Cd44 缺陷和关节内注射 HA-NP 均可保护关节软骨免受 OA 小鼠模型中 OA 的发展。发现 NF-κB 介导 CD44 诱导的分解代谢因子表达，并且 HA-NP 抑制了软骨细胞中 CD44 诱导的 NF-κB 激活。我们的研究结果确定了空的 HA-NP 作为一种针对 OA 治疗的潜在治疗剂，CD44-NF-κB-分解代谢基因轴作为破坏软骨疾病的潜在机制。
