Mechanism of Site-Specific Bone Differentiation Pathways

位点特异性骨分化途径的机制

• 批准号: 7029998
• 负责人: JINXI WANG
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029998
• 关键词: biological signal transduction; bone morphogenetic proteins; bone regeneration; cartilage; cartilage development; cell differentiation; cell growth regulation; cell proliferation; congenital oral /facial /cranial defect; developmental genetics; gene induction /repression; genetic regulation; genetically modified animals; histology; immunocytochemistry; laboratory mouse; mesenchyme; morphometry; normal ossification; osteogenesis; polymerase chain reaction; skull; stem cells; transcription factor; wound healing

DESCRIPTION (provided by applicant): Bone morphogenetic proteins (BMPs) induce bone formation during development and postnatal bone repair. Demineralized bone matrix (DBM) is the initial osteoinductive material for the isolation and purification of BMPs. Our previous studies have demonstrated that the initial cellular sequence and repair tissues induced by DBM/BMPs are distinctly different in the calvarial bone defects from those induced in the soft tissue sites. DBM-induced repair of rat calvarial defect occurs initially by the differentiation of dura-derived mesenchymal cells to osteoblasts and the direct formation of bone. In contrast, implantation of DBM into subcutaneous sites first induces cartilage cells followed by an endochondral sequence of ossification. The molecular and cellular mechanisms of site-specific differences in repair responses to DBM/BMPs are unknown. More recently, we have discovered that one member of the nuclear factor of activated T cells (NFAT) transcription factors family, NFATp (NFATc2), may be a represser of cartilage cell differentiation in adult mice. In adult mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage followed by an endochondral sequence of ossification. To our knowledge, NFATp is the first transcription factor described to control the differentiation of adult mesenchymal stem cells into cartilage. This is in contrast to the function of the cartilagespecific transcription factor Sox 9, which is critical in embryonic cartilage morphogenesis. In this application we wish to explore whether transcription factor NFATp regulates the differentiation pathways of adult mesenchymal stem cells during DBM-induced repair of cranial defects in mice. We propose 1) to detect whether NFATp expression is higher at the cranial site of normal mice, which suppresses the chondrogenic pathway at the cranial site, and 2) to determine whether lack of NFATp will alter DBM-induced bone differentiation pathways and the healing process during the repair of cranial defects. Acquiring such understanding may provide novel insight into the mechanisms of site-dependent responses to DBM/BMP implants and could possibly lead to improved therapeutic methods for the repair of skeletal tissues.

描述（由申请人提供）：骨形态发生蛋白（BMP）在发育和产后骨修复过程中诱导骨形成。脱矿质骨基质（DBM）是用于分离和纯化BMP的初始骨诱导材料。我们先前的研究表明，在颅骨缺陷中，由DBM/BMP诱导的初始细胞序列和修复组织与在软组织部位诱导的骨缺陷中截然不同。 DBM诱导的大鼠钙缺损的修复 最初是由于硬脑膜衍生的间充质细胞与成骨细胞的分化和骨的直接形成而发生的。相比之下，将DBM植入皮下位点首先诱导软骨细胞，然后诱导软骨的骨化序列。位点特异性差异在对DBM/BMP的修复反应中的分子和细胞机制尚不清楚。最近，我们发现活化T细胞（NFAT）转录因子家族NFATP（NFATC2）的一个成员可能是成年小鼠软骨细胞分化的抑制剂。在缺乏NFATP的成年小鼠中，室外结缔组织中的驻留细胞自发地与软骨区分开，然后是骨化的软骨序列。据我们所知，NFATP是对控制成年间充质干细胞分化为软骨的第一个转录因子。这与软骨特异性转录因子SOX 9的功能相反，这对于胚胎软骨形态发生至关重要。在此应用中，我们希望探索转录因子NFATP是否调节DBM诱导的小鼠颅缺损修复过程中成年间充质干细胞的分化途径。我们建议1）检测正常小鼠的颅位部位的NFATP表达是否较高，这会抑制颅位部位的软骨发作途径，以及2）确定缺乏NFATP是否会改变DBM诱导的骨骼分化途径和修复颅骨缺陷期间的愈合过程。获得这种理解可以提供对位点依赖性反应对DBM/BMP植入物的机制的新颖见解，并可能导致改进的治疗方法来修复骨骼组织。