Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development
Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development
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DOI：
10.1242/dev.00505
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发表时间：
2003-06-01
期刊：
影响因子：
4.6
通讯作者：
Lyons, KM
中科院分区：
文献类型：
--
作者：
Ivkovic, S;Yoon, BS;Lyons, KM
细胞外基质的协同产生和重塑在发育过程中至关重要。这对于骨骼发生尤其重要，因为软骨和骨骼提供结构支撑的能力是由细胞外基质的组成和组织所决定的。结缔组织生长因子（CTGF，CCN2）是一种分泌蛋白，包含几个结构域，可介导与生长因子、整合素和细胞外基质成分的相互作用。CTGF在伤口愈合过程中具有介导胶原蛋白沉积的能力，这表明它在细胞外基质产生中起作用。CTGF在体外还能诱导新血管形成，这表明它在体内血管生成中起作用。为了测试CTGF在发育过程中是否是细胞外基质重塑和/或血管生成所必需的，我们研究了Ctgf的表达模式并培育了Ctgf缺陷型小鼠。Ctgf在妊娠中期胚胎的多种组织中表达，在血管组织和成熟的软骨细胞中表达水平最高。通过培育Ctgf（-/-）小鼠，我们证实CTGF是软骨细胞外基质重塑的关键调节因子。Ctgf缺乏会导致骨骼畸形，这是由于肥大区域内软骨细胞增殖受损以及细胞外基质组成异常所致。特定细胞外基质成分和基质金属蛋白酶表达降低，表明Ctgf突变体肥大区域内的基质重塑存在缺陷。突变体表型还揭示了Ctgf在生长板血管生成中的作用。Ctgf突变生长板的肥大区域扩大，软骨内骨化受损。这些缺陷与Ctgf突变体肥大区域内血管内皮生长因子（VEGF）表达降低有关。这些结果表明，CTGF在软骨发生过程中对细胞增殖和基质重塑很重要，并且是在生长板处将细胞外基质重塑与血管生成相耦合的关键调节因子。
Coordinated production and remodeling of the extracellular matrix is essential during development. It is of particular importance for skeletogenesis, as the ability of cartilage and bone to provide structural support is determined by the composition and organization of the extracellular matrix. Connective tissue growth factor (CTGF, CCN2) is a secreted protein containing several domains that mediate interactions with growth factors, integrins and extracellular matrix components. A role for CTGF in extracellular matrix production is suggested by its ability to mediate collagen deposition during wound healing. CTGF also induces neovascularization in vitro, suggesting a role in angiogenesis in vivo. To test whether CTGF is required for extracellular matrix remodeling and/or angiogenesis during development, we examined the pattern of Ctgf expression and generated Ctgf-deficient mice. Ctgf is expressed in a variety of tissues in midgestation embryos, with highest levels in vascular tissues and maturing chondrocytes. We confirmed that CTGF is a crucial regulator of cartilage extracellular matrix remodeling by generating Ctgf(-/-) mice. Ctgf deficiency leads to skeletal dysmorphisms as a result of impaired chondrocyte proliferation and extracellular matrix composition within the hypertrophic zone. Decreased expression of specific extracellular matrix components and matrix metalloproteinases suggests that matrix remodeling within the hypertrophic zones in Ctgf mutants is defective. The mutant phenotype also revealed a role for Ctgf in growth plate angiogenesis. Hypertrophic zones of Ctgf mutant growth plates are expanded, and endochondral ossification is impaired. These defects are linked to decreased expression of vascular endothelial growth factor (VEGF) in the hypertrophic zones of Ctgf mutants. These results demonstrate that CTGF is important for cell proliferation and matrix remodeling during chondrogenesis, and is a key regulator coupling extracellular matrix remodeling to angiogenesis at the growth plate.