Merino R, Macias D, Gañan Y, Economides A N, Wang X, Wu Q, Stahl N, Sampath K T, Varona P, Hurle J M
Facultad de Medicina, Universidad de Cantabria, Santander, 39011, Spain.
Dev Biol. 1999 Feb 1;206(1):33-45. doi: 10.1006/dbio.1998.9129.
Bone morphogenetic proteins (BMPs) constitute a large family of secreted signals involved in the formation of the skeleton but the specific function of each member of this family remains elusive. GDF-5 is a member of the BMP family which has been implicated in several skeletogenic events including the induction and growth of the appendicular cartilages, the determination of joint forming regions, and the establishment of tendons. Here, we have studied the function of GDF-5 in digit skeletogenesis by analyzing the effects of its local administration in the developing autopod of embryonic chick and the regulation of its pattern of gene expression by other signals involved in digit morphogenesis. As reported in the mouse, the gdf-5 gene exhibits a precise distribution in the joint-forming regions of the developing chicken digital rays. GDF-5 beads implanted at the tip of the digits promote intense cartilage growth and fail to induce morphological or molecular signs of joint formation. Furthermore, GDF-5 beads implanted in the interdigits inhibit the formation of joints in the adjacent digits. These data suggest that the role of GDF-5 in joint formation is the control of growth and differentiation of the cartilage of the epiphyseal regions of the phalanges rather than accounting for the differentiation of the sinovial joint tissues. The interdigital mesoderm in spite of its potential to form ectopic digits with their tendinous apparatus failed to form either ectopic cartilages or ectopic tendons after the implantation of GDF-5 beads in the stages preceding cell death. At difference with other BMPs, GDF-5 exhibited only a weak cell death promoting effect. The BMP antagonist Noggin binds to GDF-5 and is able to inhibit all the observed effects of this growth factor in vivo. Potential interactions of GDF-5 with other signals involved in digits morphogenesis were also explored. BMP-7 regulates negatively the expression of gdf-5 gene in the joint forming regions and local treatment with Noggin induces the ectopic expression of gdf-5 in the interdigital mesoderm. Retroviral-induced misexpression of Indian or Sonic Hedgehog genes in the developing digits leads to the formation of digits without joints in which gdf-5 expression occurs throughout the entire perichondrial surface. In conclusion, this study indicates that GDF-5 is a signal regulated by other BMPs which controls the growth and differentiation of the epiphyses of the digital cartilages acting in close relationship with Hedgehog signaling.
骨形态发生蛋白（BMPs）构成了一个参与骨骼形成的分泌信号大家族，但该家族每个成员的具体功能仍不清楚。生长分化因子-5（GDF-5）是BMP家族的一员，与多种骨骼生成事件有关，包括附属软骨的诱导和生长、关节形成区域的确定以及肌腱的形成。在此，我们通过分析其在胚胎鸡发育中的 autopod 局部给药的影响以及其他参与指骨形态发生的信号对其基因表达模式的调控，研究了GDF-5在指骨骨骼发生中的功能。正如在小鼠中所报道的，gdf-5基因在发育中的鸡指射线的关节形成区域呈现精确分布。植入指端的GDF-5珠子促进强烈的软骨生长，且未能诱导关节形成的形态学或分子学迹象。此外，植入指间隙的GDF-5珠子抑制相邻指骨的关节形成。这些数据表明，GDF-5在关节形成中的作用是控制指骨骨骺区域软骨的生长和分化，而非滑膜关节组织的分化。尽管指间隙中胚层有形成带有肌腱装置的异位指骨的潜力，但在细胞死亡前阶段植入GDF-5珠子后，它既未形成异位软骨也未形成异位肌腱。与其他BMP不同，GDF-5仅表现出微弱的促进细胞死亡的作用。BMP拮抗剂Noggin与GDF-5结合，并能够在体内抑制该生长因子所有观察到的效应。我们还探索了GDF-5与其他参与指骨形态发生的信号之间的潜在相互作用。BMP-7在关节形成区域负向调节gdf-5基因的表达，用Noggin进行局部处理可诱导gdf-5在指间隙中胚层异位表达。在发育中的指骨中，逆转录病毒诱导的印度刺猬基因或音猬因子基因的错误表达导致无关节指骨的形成，其中gdf-5表达出现在整个软骨膜表面。总之，本研究表明GDF-5是一种受其他BMP调节的信号，它控制指骨软骨骨骺的生长和分化，并与刺猬信号密切相关。
