Salminen H, Vuorio E, Säämänen A M
University of Turku, Finland.
Arthritis Rheum. 2001 Apr;44(4):947-55. doi: 10.1002/1529-0131(200104)44:4<947::AID-ANR152>3.0.CO;2-4.
To determine the capacity of chondrocytes in aging and degenerating articular cartilage to produce major components of the extracellular matrix and maintain the normal structure of articular cartilage in a transgenic mouse model of osteoarthritis.
Transcription factor Sox9 was used as an indicator of the activation and maintenance of the articular chondrocyte phenotype. Knee joints of Del1 mice carrying 6 copies of the pro alpha1(II) collagen transgene with a short deletion mutation were analyzed at the age of 10 days and at 2, 3, 4, 6, 9, and 15 months by Northern hybridization, RNase protection assay, quantitative reverse transcription-polymerase chain reaction, and immunohistochemistry. Nontransgenic littermates were used as controls.
We demonstrated the presence of Sox9 in articular chondrocytes during development, growth, and aging, with the highest messenger RNA levels during the period of rapid growth. With the appearance of degenerative lesions in articular cartilage, 2 repair processes were observed. Local proliferation and activation of chondrocytes rich in Sox9, surrounded by type IIA procollagen and proteoglycans, was seen in articular cartilage. In contrast, metabolically inactive chondrocytes were observed at the margins of the defects. They were devoid of Sox9 and were surrounded by a proteoglycan-poor matrix. Sometimes, the lesions were filled with repair tissue that contained type III collagen but little proteoglycan or type II collagen.
The results indicate that chondrocytes in mature articular cartilage are capable of inducing the production of Sox9 and type IIA procollagen, which is typical of early chondrogenesis. Degenerative defects in the knee joints of transgenic Del1 mice are associated with local activation of chondrocytes, which probably contributes to the repair process. In other areas, the repair process produces a noncartilaginous matrix, which is insufficient to maintain the integrity of articular cartilage and which allows degeneration to proceed.
在骨关节炎转基因小鼠模型中，确定衰老和退变关节软骨中软骨细胞产生细胞外基质主要成分以及维持关节软骨正常结构的能力。
转录因子Sox9用作关节软骨细胞表型激活和维持的指标。对携带6个拷贝的前α1（II）型胶原转基因且有短缺失突变的Del1小鼠膝关节，在10日龄以及2、3、4、6、9和15月龄时，通过Northern杂交、核糖核酸酶保护分析、定量逆转录-聚合酶链反应和免疫组织化学进行分析。以非转基因同窝小鼠作为对照。
我们证实在发育、生长和衰老过程中，关节软骨细胞中存在Sox9，在快速生长阶段信使核糖核酸水平最高。随着关节软骨退变病变的出现，观察到两种修复过程。在关节软骨中可见富含Sox9的软骨细胞局部增殖和激活，周围有IIA型原胶原和蛋白聚糖。相反，在缺损边缘观察到代谢不活跃的软骨细胞。它们缺乏Sox9，周围是蛋白聚糖含量低的基质。有时，病变处充满了含有III型胶原但蛋白聚糖或II型胶原很少的修复组织。
结果表明，成熟关节软骨中的软骨细胞能够诱导产生Sox9和IIA型原胶原，这是早期软骨形成的典型特征。转基因Del1小鼠膝关节的退变缺损与软骨细胞的局部激活有关，这可能有助于修复过程。在其他区域，修复过程产生非软骨基质，不足以维持关节软骨的完整性，从而使退变继续发展。
