A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage
A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage
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DOI：
10.1242/dev.00901
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发表时间：
2004-01-01
期刊：
影响因子：
4.6
通讯作者：
Zhang, K
中科院分区：
文献类型：
--
作者：
Nakayama, N;Han, CYE;Zhang, K
我们已经鉴定出一种新的类似于Chordin的蛋白，CHL2，它在结构上与CHL/神经元/胃动素最同源。当注入非洲爪哇胚胎时，CHL2 RNA诱导了一个次生轴。重组CHL2蛋白以竞争方式直接与BMPs相互作用，阻止与I型BMP受体胞外区的结合，并抑制C2C12细胞BMP依赖的碱性磷酸酶的诱导。因此，CHL2作为一种分泌型BMP结合抑制因子发挥作用。原位杂交显示，CHL2的表达仅限于不同发育阶段关节软骨表面的软骨细胞和生殖器官中的结缔组织。成体间充质祖细胞表达CHL2，其表达水平随成软骨细胞分化而降低。在软骨细胞培养体系中加入CHL2蛋白可减少软骨基质沉积。一直以来，CHL2转录本在正常成人关节软骨中都弱检测到。然而，CHL2在骨关节炎关节软骨中的中层软骨细胞中表达上调(在那里诱导肥大标志物)。在培养的透明软骨颗粒的肥大分化过程中加入CHL2可抑制软骨细胞的矿化。因此，在发育和退变关节的透明软骨中，CHL2可能在关节软骨细胞的(重新)生成和成熟过程中发挥负面作用。
We have identified a novel chordin-like protein, CHL2, which is structurally most homologous to CHL/neuralin/ventroptin. When injected into Xenopus embryos, CHL2 RNA induced a secondary axis. Recombinant CHL2 protein interacted directly with BMPs in a competitive manner to prevent binding to the type I BMP receptor ectodomain, and inhibited BMP-dependent induction of alkaline phosphatase in C2C12 cells. Thus, CHL2 behaves as a secreted BMP-binding inhibitor. In situ hybridization revealed that CHL2 expression is restricted to chondrocytes of various developing joint cartilage surfaces and connective tissues in reproductive organs. Adult mesenchymal progenitor cells expressed CHL2, and its levels decreased during chondrogenic differentiation. Addition of CHL2 protein to a chondrogenic culture system reduced cartilage matrix deposition. Consistently, CHL2 transcripts were weakly detected in normal adult joint cartilage. However, CHL2 expression was upregulated in middle zone chondrocytes in osteoarthritic joint cartilage (where hypertrophic markers are induced). CHL2 depressed chondrocyte mineralization when added during the hypertrophic differentiation of cultured hyaline cartilage particles. Thus, CHL2 may play negative roles in the (re)generation and maturation of articular chondrocytes in the hyaline cartilage of both developing and degenerated joints.