Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects.
Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects.
复制标题
DOI：
10.1038/srep29814
复制
发表时间：
2016-07-13
影响因子：
4.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Ma P;Yan W;Tian Y;Wang J;Feng JQ;Qin C;Cheng YS;Wang X
在软骨内骨化过程中，软骨细胞在增殖-成熟过渡期间将自身嵌入富含蛋白多糖的基质中。越来越多的证据表明，蛋白多糖是软骨细胞增殖和分化的重要组成部分。当我们使用Osr 2-Cre从牙间充质中条件性灭活FAM 20 B（具有序列相似性20成员-B的家族）时，我们发现膝关节中的软骨肉瘤和长骨中出生后骨化的显著缺陷，FAM 20 B是一种新鉴定的木糖激酶，其对于蛋白聚糖的蛋白核心上的糖胺聚糖（GAG）形成是必需的，Osr 2-Cre也在关节软骨中强烈表达。机制分析显示，缺陷与骺软骨细胞中多个信号传导途径的功能获得相关，例如WNT、BMP和PTHrP/IHH分子衍生的信号传导途径，表明FAM 20 B催化的蛋白聚糖是控制软骨细胞分化和增殖的调控网络中信号传导平衡的关键介质。特别是，我们证明了WNT抑制剂能够挽救Osr 2-Cre; Fam 20 Bfl/fl小鼠中的部分骨缺损，表明FAM 20 B催化的蛋白多糖部分通过WNT信号转导介导调节出生后软骨内骨化。
During endochondral ossification, chondrocytes embed themselves in a proteoglycan-rich matrix during the proliferation-maturation transition. Accumulating evidence shows that proteoglycans are essential components for chondrocyte proliferation and differentiation. When we conditionally inactivated FAM20B (Family with sequence similarity 20 member-B), which is a newly identified xylose kinase essential for glycosaminoglycan (GAG) formation on the protein core of proteoglycans, from the dental mesenchyme using Osr2-Cre, which is also strongly expressed in joint cartilage, we found chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones. Mechanistic analysis revealed that the defects were associated with gain of function in multiple signaling pathways in the epiphyseal chondrocytes, such as those derived by WNT, BMP, and PTHrP/IHH molecules, suggesting that the FAM20B-catalyzed proteoglycans are critical mediators for a signaling balance in the regulatory network controlling chondrocyte differentiation and proliferation. In particular, we demonstrated that the WNT inhibitor was able to rescue part of the bone defects in Osr2-Cre;Fam20Bfl/fl mice, indicating that FAM20B-catalyzed proteoglycans regulate postnatal endochondral ossification partially through the mediation of WNT signaling.