Igf signaling control of chondrocyte hypertrophy in bone development and repair

 描述（由申请人提供）：脊椎动物骨骼成分的发育需要精确控制细胞生长和大小。脊椎动物的所有长骨都是通过软骨内骨化形成的，其中骨由软骨细胞前体形成。在这个过程中，软骨细胞经历肥大，以延长发育中的骨。最近，在这些软骨细胞中发现了三个不同的肥大阶段，并且发现胰岛素生长因子（IGF）依赖性第三阶段的差异是导致骨长度差异的原因。这些发现开启了关于骨骼发育和修复以及导致骨骼元素缩短的病理学的几个问题。IGF信号如何调节软骨细胞肥大仍然知之甚少，特别是介导这一过程的下游靶点是什么。此外，在骨折修复过程中，软骨细胞比发育过程中观察到的更大。在这种情况下，软骨细胞肥大的动力学尚未研究，目前仍不清楚这是否真正重演的发展，或者是否采用替代机制。最后，多种遗传性疾病会导致四肢长骨缩短。尽管对这些疾病背后的遗传原因有所了解，但导致骨骼缩短的机制尚不清楚。因此，本研究的目的是检查IGF信号在软骨细胞肥大的发展和骨折修复过程中。最后，本研究将调查软骨细胞肥大的动力学在小鼠模型的骨骼疾病，导致肢体缩短。为了验证以下假设：（1）IGF信号通路的下游转录靶介导软骨细胞肥大。(2)骨折后的修复需要IGF依赖性软骨细胞肥大和（3）导致长骨缩短的遗传病理学缺乏软骨细胞肥大的特定阶段。我提出以下目标。具体目标1：确定介导软骨细胞肥大的IGF信号转导的靶点。具体目标2：研究骨修复中肥大软骨细胞的生长和IGF信号依赖性。具体目标3：评估导致肢体缩短的遗传性疾病小鼠模型中的软骨细胞大小和动力学。这些实验的成功完成将产生一个更完整的了解IGF信号和它如何控制骨骼形态。此外，这项研究的发现将拓宽我们对骨修复和再生的认识，并为发育性骨病提供潜在的治疗靶点。

 DESCRIPTION (provided by applicant): Development of the skeletal elements in vertebrates requires precise control over cell growth and size. All long bones of vertebrates are formed via endochondral ossification where bone forms from chondrocyte precursors. During this process, chondrocytes undergo hypertrophy in order to elongate the developing bone. Recently, three distinct phases of hypertrophy were discovered in these chondrocytes and differences in the Insulin growth factor (IGF)-dependent third phase were found to be responsible for differences in bone lengths. These findings open several questions on bone development and repair as well as pathologies that result in shortened skeletal elements. How IGF signaling regulates chondrocyte hypertrophy remains poorly understood, specifically what the downstream targets are that mediate this process. Further, during fracture repair, chondrocytes enlarge more than that observed during development. The dynamics of chondrocyte hypertrophy in this context have not been investigated and it remains unclear if this truly recapitulates development or if alternative mechanisms are employed. Finally, multiple genetic disorders result in shortened long bones of the limbs. Despite an understanding of the genetic cause behind some of these disorders, the mechanisms that result in shortened bones is not known. Therefore, the objectives of this study are to examine IGF signaling in chondrocyte hypertrophy during development and fracture repair. Finally, this study will investigate chondrocyte hypertrophy dynamics in mouse models for skeletal diseases that result in shortened limbs. In order to test the following hypotheses: (1) Downstream transcriptional targets of the IGF signaling pathway mediate hypertrophy in chondrocytes. (2) Repair following bone fracture requires IGF dependent chondrocyte hypertrophy and (3) Genetic pathologies that result in shortened long bones lack specific phases of chondrocyte hypertrophy. I propose the following aims. Specific Aim 1: Determine the targets of IGF signaling that mediate chondrocyte hypertrophy. Specific Aim 2: Investigate the growth of hypertrophic chondrocytes and IGF signaling dependence in repairing bone. Specific Aim 3: Assess chondrocyte size and dynamics in mouse models of genetic disorders that result in shortened limbs. The successful completion of these experiments will generate a more complete understanding of IGF signaling and how it controls skeletal morphology. Further, findings from this study will broaden our knowledge of bone repair and regeneration as well as suggest potential therapeutic targets for developmental bone diseases.