Laboratory of Experimental Trauma Surgery, Department of Trauma Surgery, University Hospital Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany.
Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, OP31, Portland, OR 97239, USA.
Cells. 2019 Aug 20;8(8):936. doi: 10.3390/cells8080936.
Osteoarthritis (OA) is a degenerative condition that involves the production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)) that stimulate degradative enzymes, matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) resulting in articular cartilage breakdown. The presence of interleukin-1β (IL-1β) is one reason for poor clinical outcomes in current cell-based tissue engineering strategies for treating focal early osteoarthritic defects. Mesenchymal stem cells (MSCs) are a potential cell source for articular cartilage regeneration, although IL-1β has been shown to inhibit in vitro chondrogenesis. In vivo, articular chondrocytes reside under a low oxygen environment between 2-5% oxygen (physioxia) and have been shown to enhance in vitro MSC chondrogenic matrix content with reduced hypertrophic marker expression under these conditions. The present investigation sought to understand the effect of physioxia on IL-1β inhibited MSC chondrogenesis. MSCs expanded under physioxic (2% oxygen) and hyperoxic (20%) conditions, then chondrogenically differentiated as pellets in the presence of TGF-β1 and either 0.1 or 0.5 ng/mL IL-1β. Results showed that there were donor variations in response to physioxic culture based on intrinsic GAG content under hyperoxia. In physioxia responsive donors, MSC chondrogenesis significantly increased GAG and collagen II content, whilst hypertrophic markers were reduced compared with hyperoxia. In the presence of IL-1β, these donors showed a significant increase in cartilage matrix gene expression and GAG content relative to hyperoxic conditions. In contrast, a set of MSC donors were unresponsive to physioxia and showed no significant increase in matrix production independent of IL-1β presence. Thus, physioxia has a beneficial effect on MSC cartilage matrix production in responsive donors with or without IL-1β application. The mechanisms controlling the MSC chondrogenic response in both physioxia responsive and unresponsive donors are to be elucidated in future investigations.
骨关节炎（OA）是一种退行性疾病，涉及炎症细胞因子（如白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6））的产生，这些细胞因子刺激降解酶、基质金属蛋白酶（MMPs）和聚集素酶（ADAMTS），导致关节软骨降解。白细胞介素-1β（IL-1β）的存在是当前基于细胞的组织工程策略治疗局灶性早期骨关节炎缺陷的不良临床结果的原因之一。间充质干细胞（MSCs）是关节软骨再生的潜在细胞来源，尽管 IL-1β 已被证明抑制体外软骨形成。在体内，关节软骨细胞存在于 2-5%氧气（低氧）的低氧环境中，并且已经表明在这些条件下可以增强体外 MSC 软骨形成基质含量，并减少肥大标志物的表达。本研究旨在了解低氧对 IL-1β 抑制 MSC 软骨形成的影响。MSCs 在低氧（2%氧气）和高氧（20%氧气）条件下扩增，然后在 TGF-β1 和 0.1 或 0.5ng/ml IL-1β存在下作为球状体进行软骨分化。结果表明，基于高氧下的内在 GAG 含量，MSCs 对低氧培养的反应存在供体差异。在对低氧有反应的供体中，MSC 软骨形成显著增加 GAG 和胶原 II 含量，而与高氧相比，肥大标志物减少。在 IL-1β存在的情况下，与高氧条件相比，这些供体的软骨基质基因表达和 GAG 含量显著增加。相比之下，一组 MSC 供体对低氧无反应，无论 IL-1β 存在与否，基质产生均无显著增加。因此，低氧对有反应和无反应供体的 MSC 软骨基质产生均有有益影响，无论是否应用 IL-1β。在有反应和无反应的供体中，控制 MSC 软骨形成反应的机制有待进一步研究。
