Garciadiego-Cázares David, Rosales Carlos, Katoh Masaru, Chimal-Monroy Jesús
Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Development. 2004 Oct;131(19):4735-42. doi: 10.1242/dev.01345. Epub 2004 Aug 25.
The control point by which chondrocytes take the decision between the cartilage differentiation program or the joint formation program is unknown. Here, we have investigated the effect of alpha5beta1 integrin inhibitors and bone morphogenetic protein (BMP) on joint formation. Blocking of alpha5beta1 integrin by specific antibodies or RGD peptide (arginine-glycine-aspartic acid) induced inhibition of pre-hypertrophic chondrocyte differentiation and ectopic joint formation between proliferating chondrocytes and hypertrophic chondrocytes. Ectopic joint expressed Wnt14, Gdf5, chordin, autotaxin, type I collagen and CD44, while expression of Indian hedgehog and type II collagen was downregulated in cartilage. Expression of these interzone markers confirmed that the new structure is a new joint being formed. In the presence of BMP7, inhibition of alpha5beta1 integrin function still induced the formation of the ectopic joint between proliferating chondrocytes and hypertrophic chondrocytes. By contrast, misexpression of alpha5beta1 integrin resulted in fusion of joints and formation of pre-hypertrophic chondrocytes. These facts indicate that the decision of which cell fate to make pre-joint or pre-hypertrophic is made on the basis of the presence or absence of alpha5beta1 integrin on chondrocytes.
软骨细胞在软骨分化程序或关节形成程序之间做出抉择的控制点尚不清楚。在此，我们研究了α5β1整合素抑制剂和骨形态发生蛋白（BMP）对关节形成的影响。用特异性抗体或RGD肽（精氨酸-甘氨酸-天冬氨酸）阻断α5β1整合素可诱导抑制前肥大软骨细胞分化，并在增殖软骨细胞和肥大软骨细胞之间异位形成关节。异位关节表达Wnt14、Gdf5、脊索蛋白、自分泌运动因子、I型胶原蛋白和CD44，而印度刺猬因子和II型胶原蛋白在软骨中的表达下调。这些中间区标志物的表达证实新结构是正在形成的新关节。在BMP7存在的情况下，抑制α5β1整合素功能仍可诱导增殖软骨细胞和肥大软骨细胞之间异位关节的形成。相比之下，α5β1整合素的错误表达导致关节融合和前肥大软骨细胞的形成。这些事实表明，软骨细胞上α5β1整合素的有无决定了细胞走向关节前或前肥大状态的命运抉择。
