Notch Signaling in Endochondral Bone Development

软骨内骨发育中的Notch信号传导

• 批准号: 10480088
• 负责人: Matthew J. Hilton
• 金额: $ 35.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480088
• 关键词: Adipocytes; Apoptosis; Biological Assay; Biology; Blood Vessels; Bone Development; Bone Marrow; Bone Matrix; Cartilage; Cartilage Matrix; Cell Therapy; Cells; Chondrocytes; Clone Cells; Data; Development; Epiphysial cartilage; Excision; Exhibits; Freezing; Generations; Genes; Genetic Models; Genotype; Goals; Histology; In Vitro; Invaded; Label; Mediating; Mesenchymal; Molecular; Mus; Orthopedics; Osteoblasts; Osteogenesis; Outcome Measure; Paraffin; Pathway interactions; Physiologic Ossification; Play; Population; Process; Regenerative Medicine; Regulation; Role; Signal Transduction; Stains; System; Therapeutic; Tissues; Work; base; bone; bone repair; cartilage cell; cell type; experimental study; gain of function; in vivo; loss of function; microCT; mouse genetics; notch protein; novel; novel strategies; osteoblast differentiation; osteogenic; overexpression; progenitor; recruit; regenerative cell; skeletal; skeletal disorder; stem; stem cells; transcriptome sequencing; transdifferentiation

PROJECT SUMMARY: A primary function of growth plate cartilage is to support bone formation and elongation during endochondral ossification. Growth plate chondrocytes undergo rapid proliferation and matrix synthesis followed by hypertrophic differentiation. Hypertrophic chondrocytes secrete various factors that degrade the cartilage matrix, recruit vascular cells and osteoblast progenitors, and promote the differentiation of osteoblasts responsible for new bone formation. Dogma dictates that hypertrophic chondrocytes ultimately undergo apoptosis to facilitate removal of the cartilage template that is eventual replaced by bone. Recent cartilage-specific lineage tracing studies have suggested that terminal hypertrophic chondrocytes are capable of directly differentiating into mature osteoblasts during bone formation and repair via a process known as transdifferentiation. However, our preliminary data suggests that at least a subset of terminal hypertrophic chondrocytes undergo dedifferentiation to generate bone marrow mesenchymal stem/progenitor cells (BMSCs) capable of differentiating into various mature cell types including: osteoblasts and adipocytes. Since almost nothing is known about this process, our long-term goal is to identify the cellular and molecular mechanism(s) that regulate hypertrophic chondrocyte dedifferentiation during endochondral bone formation. Using a variety of sophisticated mouse genetic models and in vitro systems, we aim to: (Aim 1) identify whether hypertrophic chondrocytes dedifferentiate to form a molecularly and functionally distinct population of multipotent BMSCs, (Aim 2) determine whether NOTCH signaling in hypertrophic chondrocytes is necessary and/or sufficient to promote chondrocyte dedifferentiation during endochondral bone formation, and (Aim 3) establish whether SOX2 is an important regulator of hypertrophic chondrocyte dedifferentiation and a target of NOTCH signaling in the regulation of this process. Completion of these aims will have broad implications in skeletal biology by elucidating fundamental cellular and molecular mechanisms associated with the novel process of hypertrophic chondrocyte dedifferentiation during endochondral ossification. This work will also aid our understanding of NOTCH-related skeletal diseases, as well as, set the stage for developing novel approaches for the ex vivo generation of mesenchymal stem/progenitors from cartilage for use in regenerative medicine or cell therapeutic applications.

项目总结： 生长板软骨的主要功能是支持软骨内骨的形成和伸长。 骨化。生长板软骨细胞经历快速增殖和基质合成，然后肥大 差异化。肥大的软骨细胞分泌各种因子，降解软骨基质，招募血管 并促进负责新骨形成的成骨细胞的分化。 Dogma规定，肥大的软骨细胞最终会发生凋亡，以促进软骨的去除 最终被骨骼替换的模板。最近的软骨特异性谱系追踪研究表明， 终末肥大的软骨细胞在成骨过程中能够直接分化为成熟的成骨细胞 通过一个称为转分化的过程形成和修复。然而，我们的初步数据表明，至少 终末肥大软骨细胞亚群经历去分化形成骨髓间充质 干细胞/祖细胞(BMSCs)能够分化为各种成熟细胞类型，包括：成骨细胞和 脂肪细胞。由于对这一过程几乎一无所知，我们的长期目标是确定细胞和 软骨内骨肥大细胞脱分化调控的分子机制(S) 队形。利用各种复杂的小鼠遗传模型和体外系统，我们的目标是：(目标1)识别 肥大的软骨细胞是否去分化以形成分子和功能上不同的软骨细胞群 多潜能BMSCs，(目标2)确定肥大软骨细胞中的Noch信号是否必要和/或 足以在软骨内骨形成过程中促进软骨细胞去分化，以及(目标3)确定 SOX2是肥大软骨细胞去分化的重要调节因子，也是Notch信号转导的靶点。 对这一过程的监管。通过阐明这些目标的完成，将在骨骼生物学中产生广泛的影响 肥大软骨细胞新过程的基本细胞和分子机制 软骨内骨化过程中的去分化。这项工作也将有助于我们对缺口相关骨骼的理解 疾病，以及为开发体外培养间充质细胞的新方法奠定了基础 用于再生医学或细胞治疗应用的软骨干/祖细胞。

项目成果

Cell type-specific effects of Notch signaling activation on intervertebral discs: Implications for intervertebral disc degeneration.

• DOI: 10.1002/jcp.26385
• 发表时间: 2018-07
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Zheng Y;Liu C;Ni L;Liu Z;Mirando AJ;Lin J;Saijilafu;Chen D;Hilton MJ;Li B;Chen J
• 通讯作者: Chen J

Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner.

• DOI: 10.1126/scisignal.abn7082
• 发表时间: 2022-07-26
• 期刊: Science signaling
• 影响因子: 7.3

Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget's Disease of Bone.

• DOI: 10.3390/cells12070981
• 发表时间: 2023-03-23
• 期刊: Cells
• 影响因子: 6

Whole Mount In Situ Hybridization in Murine Tissues.

小鼠组织中的整体原位杂交。

• DOI: 10.1007/978-1-0716-1028-2_22
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Sharma,Deepika;Hilton,MatthewJ;Karner,CourtneyM
• 通讯作者: Karner,CourtneyM

Magic angle effect on diffusion tensor imaging in ligament and brain.

• DOI: 10.1016/j.mri.2022.06.008
• 发表时间: 2022-10
• 期刊: MAGNETIC RESONANCE IMAGING
• 影响因子: 2.5
• 作者: Wang, Nian;Wen, Qiuting;Maharjan, Surendra;Mirando, Anthony J.;Qi, Yi;Hilton, Matthew J.;Spritzer, Charles E.
• 通讯作者: Spritzer, Charles E.