Igf signaling control of chondrocyte hypertrophy in bone development and repair

骨发育和修复中软骨细胞肥大的 Igf 信号控制

• 批准号: 9042838
• 负责人: John Joseph Young
• 金额: $ 5.61万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042838
• 关键词: Affect; American; Animals; Appearance; Bone Development; Bone Diseases; Bone Lengthening; Bone Regeneration; Bone Tissue; Cell Cycle; Cell Density; Cell Differentiation process; Cell Proliferation; Cell Size; Cells; Chondrocytes; Chromatin; Coin; Defect; Dependence; Development; Developmental Bone Diseases; Disease; Distal; Elements; Embryonic Development; Epiphysial cartilage; Extracellular Matrix; Fracture; Fracture Healing; Genetic; Growth; Hereditary Disease; Human; Hypertrophy; IGF1 gene; Indium; Insulin; Invaded; Knowledge; Lateral; Length; Limb structure; Measures; Mediating; Mesenchymal; Mesoderm; Microscopy; Molecular; Morphology; Mus; Natural regeneration; Neural Crest; Nucleosomes; Osteoblasts; Osteogenesis; Pathology; Pattern; Phase; Process; Proliferating; Recombinants; Role; Signal Pathway; Signal Transduction; Site; Skeletal Development; Skeletal system; Skeleton; Technology; Testing; Therapeutic; Vertebrates; bone; cell growth; clavicle; cranium; flat bone; intramembranous bone formation; long bone; mineralization; mouse model; mutant; public health relevance; repaired; research study; skeletal; skeletal disorder; skeletogenesis; therapeutic target; transcriptome; transcriptome sequencing

 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.

 描述（由申请人提供）：脊椎动物骨骼元件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。在此过程中，软骨细胞发生肥大，以延长正在发育的骨骼。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造成骨长度差异的原因。这些发现提出了有关骨骼发育和修复以及导致骨骼元件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标是什么。此外，在骨折修复过程中，软骨细胞的增大程度比发育过程中观察到的要大。在这种情况下软骨细胞肥大的动态尚未得到研究，并且尚不清楚这是否真正概括了发育或是否采用了替代机制。最后，多种遗传性疾病导致四肢长骨缩短。尽管了解其中一些疾病背后的遗传原因，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发育和骨折修复过程中软骨细胞肥大中的 IGF 信号传导。最后，这项研究将研究导致四肢缩短的骨骼疾病小鼠模型中的软骨细胞肥大动态。为了检验以下假设：（1）IGF信号通路的下游转录靶标介导软骨细胞肥大。 (2) 骨折后的修复需要 IGF 依赖性软骨细胞肥大，以及 (3) 导致长骨缩短的遗传病理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 信号传导靶点。具体目标 2：研究肥大软骨细胞的生长和骨修复中 IGF 信号依赖性。具体目标 3：评估导致四肢缩短的遗传性疾病小鼠模型中的软骨细胞大小和动态。这些实验的成功完成将使人们对 IGF 信号传导及其如何控制骨骼形态有更全面的了解。此外，这项研究的结果将拓宽我们对骨修复和再生的认识，并提出发育性骨疾病的潜在治疗靶点。