University of Occupational and Environmental Health, Kitakyushu, Japan, and Mitsubishi Tanabe Pharma, Osaka, Japan.
Arthritis Rheumatol. 2015 May;67(5):1250-60. doi: 10.1002/art.39036.
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes. Articular cartilage contains MSC-like chondroprogenitor cells, which suggests their involvement in the maintenance of cartilage homeostasis by a self-repair mechanism. Interleukin-6 (IL-6) is a cytokine with a wide range of physiologic functions, which are produced by MSCs in a steady manner and in large quantities. The purpose of this study was to investigate the involvement of IL-6 signaling in MSC differentiation into chondrocytes.
Human bone marrow-derived MSCs were cultured using a pellet culture system in medium containing transforming growth factor β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.
IL-6 was detected at a high concentration in culture supernatants during chondrogenic differentiation. The expression of the IL-6 receptor (IL-6R) was significantly increased, accompanied by markedly increased phosphorylation and expression of STAT-3. Addition of IL-6 and soluble IL-6R (sIL-6R) to the chondrogenic culture resulted in concentration-dependent increases in cartilage matrix accumulation and cartilage marker gene expression (type II collagen/aggrecan/type X collagen). Phosphorylation of the master transcription factor SOX9 was enhanced upon addition of IL-6 and sIL-6R. STAT-3 knockdown suppressed chondrogenic differentiation. IL-6 and the MSC markers CD166 and nestin were colocalized in macroscopically normal human cartilage taken from the lateral femoral compartment of knees with medial tibiofemoral osteoarthritis.
During differentiation of human MSCs into chondrocytes, the activation of IL-6/STAT-3 signaling positively regulated chondrogenic differentiation. The presence of IL-6 around MSC-like cells in the cartilage tissue was identified, suggesting that IL-6 contributes to homeostasis and cartilage self-repair by promoting chondrogenic differentiation.
间充质干细胞（MSCs）是多能细胞，可以分化为软骨细胞。关节软骨含有类似于 MSC 的软骨祖细胞，这表明它们通过自我修复机制参与软骨稳态的维持。白细胞介素 6（IL-6）是一种具有广泛生理功能的细胞因子，由 MSC 以稳定的方式大量产生。本研究旨在探讨 IL-6 信号在 MSC 向软骨细胞分化中的作用。
采用微球体培养系统，在含有转化生长因子 β3 的培养基中培养人骨髓来源的 MSCs。通过软骨基质积累和软骨标志物基因表达检测软骨分化。
在软骨分化过程中，IL-6 在培养上清液中以高浓度检测到。IL-6 受体（IL-6R）的表达显著增加，同时 STAT-3 的磷酸化和表达也明显增加。向软骨分化培养物中添加 IL-6 和可溶性 IL-6R（sIL-6R），可引起软骨基质积累和软骨标志物基因表达（Ⅱ型胶原/聚集蛋白/Ⅹ型胶原）呈浓度依赖性增加。添加 IL-6 和 sIL-6R 可增强主转录因子 SOX9 的磷酸化。STAT-3 敲低抑制软骨分化。IL-6 和 MSC 标志物 CD166 和 nestin 在来自内侧胫骨股骨骨关节炎膝关节外侧股骨间隔的大体正常人类软骨中均与 MSC 样细胞共定位。
在人 MSC 向软骨细胞分化过程中，IL-6/STAT-3 信号的激活正向调节软骨分化。在软骨组织中鉴定到 IL-6 周围存在 MSC 样细胞，表明 IL-6 通过促进软骨分化来促进软骨稳态和软骨自我修复。
