Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation
Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation
复制标题
DOI：
10.1002/jcp.20637
复制
发表时间：
2006-07-01
影响因子：
5.6
通讯作者：
Lian, Jane B.
中科院分区：
文献类型：
--
作者：
Gaur, Tripti;Rich, Lillian;Lian, Jane B.
经典Wnt信号传导（β-连环蛋白/TCF）已成为骨骼发生的关键调节因子。在这项研究中，在小鼠模型中检查软骨形成，其中Wnt拮抗剂分泌的卷曲相关蛋白1（sFRP 1）是非功能性的，并通过骨形成所必需的Runx 2转录因子的经典途径导致高骨量表型和活化。我们发现在出生后快速生长期间，sFRP 1（-/-）小鼠的生长板高度缩短，肥大区（HZ）钙化增加，表明加速的软骨内骨化。使用诱导成软骨细胞系的小鼠胚胎成纤维细胞（MEF），与WT细胞相比，观察到sFRP 1（-/-）MFF中软骨形成增加和肥大软骨细胞分化加速。sFRP 1（-/-）MEFs中肥大软骨细胞的诱导成熟与磷酸-β-连环蛋白水平呈负相关，表明参与了以2a 1型胶原和Sox 9表达增加为特征的活化经典Wnt信号传导。然而，没有发现在WT细胞中表达的Indian hedgehog。SFRP 1（-/-）细胞也表现出10a 1型胶原的早期诱导。因此，这些基因表达的修饰是SFRP 1（-/-）细胞中软骨细胞分化增加的机制。这些研究已经确定sFRP 1是软骨细胞分化正常进程中Wnt信号传导的关键负调节因子。微阵列基因分析提供了额外的新的见解，适当的Wnt信号的控制软骨细胞成熟所必需的调节因子。
Canonical Wnt signaling (beta-catenin/TCF) has emerged as a key regulator of skeletogenesis. In this study, chondrogenesis is examined in a mouse model in which the Wnt antagonist secreted frizzled related protein 1 (sFRP1) is non-functional and results in a high bone mass phenotype and activation through the canonical pathway of the Runx2 transcription factor that is essential for bone formation. We find during the period of rapid post-natal growth, shortened height of the growth plate and increased calcification of the hypertrophic zone (HZ) in the sFRP1(-/-) mouse, indicating accelerated endochondral ossification. Using mouse embryo fibroblasts (MEFs) induced into the chondrogenic lineage, increased chondrogenesis and accelerating differentiation of hypertrophic chondrocytes in the sFRP1(-/-) MFFs was observed compared to WT cells. The induced maturation of hypertrophic chondrocytes in sFRP1(-/-) MEFs was inversely correlated to phospho-beta-catenin levels, indicating involvement of activated canonical Wnt signaling characterized by an increased expression of collagen type 2a1 and Sox 9. However, an absence of Indian hedgehog expression Which Occurs in WT cells was found. SFRP1(-/-) cells also exhibited an early induction of collagen type 10a1. Thus, these modifications in gene expression are contributing mechanism(s) for increased chondrocyte differentiation in SFRP1(-/-) cells. These Studies have identified sFRP1 as a critical negative regulator of Wnt signaling for the normal progression of chondrocyte differentiation. Microarray gene profiling provided additional novel insights into the regulatory factors for appropriate Wnt signaling necessary for the control of chondrocyte maturation.