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Atf4 in Chondrocytes Regulates Cartilage to Bone Transition

软骨细胞中的 Atf4 调节软骨到骨的转变

基本信息

批准号：
9028617
负责人：
XIANGLI YANG
金额：
$ 34.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-18 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028617
关键词：
Address Adult Affect Age Animal Model Animals Atrophic Birth Blood Vessels Bone Injury Bone Regeneration Bone callus Bone remodeling Cartilage Chondrocytes Complication Coupling Defect Degenerative polyarthritis Development Diaphyses Disease Dwarfism Elderly Epiphysial cartilage Erinaceidae Etiology Failure Family Fetal Development Fetal Growth Fracture Fracture Healing Genetic Genetic Transcription Growth Growth Factor Healed Health Hormones Hypertrophy Injury Invaded Laboratories Lead Life Ligands Mechanics Medical Mesenchymal Modeling Molecular Morbidity - disease rate Mus Necrosis Nuclear Operative Surgical Procedures Osteoblasts Osteocalcin Osteoclasts Osteogenesis Osteopenia Osteoporosis Persistent pain Phase Physical condensation Physiological Processes Play Process Regulation Role Signal Transduction Skeletal Development Skeleton Somatotropin Staging Stress United States Weight-Bearing state Work bone bone mass cost cytokine gain of function healing injured insight long bone mortality mutant osteoblast differentiation public health relevance receptor repaired restoration skeletal skeletal disorder stem success tibia transcription factor

项目摘要

DESCRIPTION (provided by applicant): Fractures are a common injury in the United States and can lead to severe morbidity, high medical costs and significant mortality, especially in the elderly. Failures of healing, including cases of nonunion, secondary displacement and avascular necrosis, require repeated invasive surgery with decreased success rate with subsequent surgeries. The etiology underlying such bone repair failures is unknown but can be informed by a better understanding of the molecular mechanisms regulating endochondral ossification that includes mesenchymal condensation, chondrocyte differentiation and hypertrophy to form a cartilaginou anlagen that is then invaded by blood vessels, which brings osteoblasts and osteoclasts to form bone. Each step during endochondral ossification is tightly controlled by a number of growth hormones, cytokines and transcription factors. Work from our laboratory identified a transcription factor of the Creb family Atf4 that regulates chondrocyte proliferation, differentiation, and osteoblast maturation via activating the transcription of Indian hedgehog (Ihh), receptor activator of nuclear factor-κB ligand (Rankl) and osteocalcin (Ocn), respectively. Global Atf4 deficiency (Atf4-/-) led to dwarfism and severe osteopenia in mice. Surprisingly, restoration of Atf4 expression specifically in chondrocytes of the Atf4-/- mice not only completely rescued their size but also their bone mass defects. This finding strongly suggests that Atf4 in chondrocytes (chAtf4), but not it in osteoblasts (obAtf4), plays an indispensible role in the control of endochondral ossification and the chAtf4 is critical to the coupling between growth plate elongation and bone mass accrual after birth. What remains to be understood is how the chAtf4 versus the obAtf4, influences the set of hormones, growth factors, cytokines, and transcription factors involved in bone modeling and remodeling. Our central hypothesis is that chAtf4 is a critical transcriptional homeostat for the harmonious coupling between cartilage formation and bone modeling during development and bone repair. We propose the following specific aims to address this hypothesis using animal models. Aim 1. To determine whether chAtf4 controls the conversion of cartilage to bone via its regulation of Mmp13 and Rankl transcription. Aim 2. To elucidate whether obAtf4 is necessary for bone remodeling in adults. Aim 3. To determine whether Atf4 is required in adults for proper transition between the phases of endochondral bone repair. Impact. Among the osteoblast differentiation factors Atf4 is unique for studies focusing on the regulators of cartilage to bone transition because its null mutants survive postnatally and it is expressed in all the subpopulation of chondrocytes. Thus the temporal and spatial function of Atf4 will provides us a unique opportunity to gain insights into mechanisms underlying the physiological processes during skeletal development and pathological conditions in fracture repair, nonunion, osteoarthritis.