Regulation of Mandibular Condylar Cartilage Growth

下颌髁软骨生长的调节

• 批准号: 6686165
• 负责人: ROBERT J HINTON
• 金额: $ 28.37万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-07 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686165
• 关键词: cartilage development; cell adhesion molecules; cell growth regulation; cell proliferation; cell surface receptors; fibroblast growth factor; gene expression; genetic regulation; genetically modified animals; laboratory mouse; mandibular condyle; periosteums; procollagen; protein localization; skull; stem cells; temporomandibular joint syndrome; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): The long-term goal of this application is to better understand how proliferation and growth at the mandibular condylar cartilage (MCC) is regulated and if it is different from growth in the primary cartilage (growth plate) of limbs. This understanding can be exploited to devise better treatment strategies for growth problems and persistent inflammatory disorders at the temporomandibular joint. Relatively little is known of how the molecular determinants of growth differ among cranial sutures, mandibular condylar cartilage, and the cranial base cartilages. Recent studies have provided clues that regulation of proliferation in the MCC may be more similar to that in cranial sutures than in limb cartilage. Accordingly, it is possible that proliferation and differentiation in MCC are regulated by mechanisms common to periosteum, not cartilage. We hypothesize that chondroprogenitor cells of the mandibular condylar cartilage and osteoprogenitor cells of cranial sutures share regulatory molecules and receptors, distinct from the proliferative chondrocytes of primary cartilage. This hypothesis will be tested by three specific aims: 1) In explant culture, establish localization of downstream mediators of Fgf-2 and Tgf-Beta2 activity (Twist and Dachl) in MCC, cranial suture (SUT), and the primary cartilage of the sphenooccipital synchondrosis (SOS). We will test the hypothesis that mediators of Fgf2 and Tgf-Beta2 activity are the same in MCC and SUT, and that they differ from mediators of Fgf2 and Tgf-Beta2 activity in SOS; 2) Establish whether removal of the periosteum from MCC, SUT, and SOS explants enhances or inhibits the expression of Twist or Dachl. We will test the hypothesis that the periosteum produces factors that modulate Twist and Dachl expression and activity differently in MCC, SUT, and SOS; 3) Test the findings of the explant studies in appropriate knockout mouse strains. We will test the hypothesis that reduction or elimination of specific mediators of Fgf2 or Tgf-Beta2 activity in vivo (Twist and Fgfr2HIc) has downstream consequences for MCC and SUT that are distinct from those in SOS. This information is critical, as most concepts of temporomandibular joint dysfunction (TMD) approach the TMJ as a synovial joint containing a typical articular cartilage. If the perichondrial cells in MCC share regulatory features with cells in SUT rather than in SOS, this assumption is not only erroneous but may lead to inappropriate treatment strategies.

描述（由申请人提供）：本申请的长期目标是更好地了解下颌髁突软骨（MCC）的增殖和生长是如何受到调节的，以及它是否与四肢初级软骨（生长板）的生长不同。这种理解可以用来设计更好的治疗策略，以解决生长问题和持续的颞下颌关节炎症性疾病。对于颅缝线、下颌髁软骨和颅基底软骨之间生长的分子决定因素的差异，我们所知的相对较少。最近的研究提供了线索，MCC的增殖调节可能更类似于颅缝，而不是肢体软骨。因此，MCC的增殖和分化可能是由骨膜共同的机制调节的，而不是软骨。我们假设下颌髁突软骨的软骨祖细胞和颅骨缝合线的骨祖细胞共享调节分子和受体，不同于原代软骨的增殖软骨细胞。这一假设将通过三个具体目标来验证：1)在外植体培养中，在MCC、颅缝（SUT）和枢枕软骨联合（SOS）的初级软骨中建立Fgf-2和tgf - β 2活性的下游介质（Twist和Dachl）的定位。我们将检验MCC和SUT中Fgf2和Tgf-Beta2活性的介质是相同的，而它们与SOS中Fgf2和Tgf-Beta2活性的介质不同的假设；2)确定从MCC、SUT和SOS外植体去除骨膜是否增强或抑制Twist或Dachl的表达。我们将检验骨膜产生调节Twist和Dachl在MCC、SUT和SOS中不同表达和活性的因子的假设；3)在合适的敲除小鼠品系中检验外植体研究结果。我们将验证以下假设，即体内Fgf2或tgf - β 2活性的特定介质（Twist和Fgfr2HIc）的减少或消除对MCC和SUT具有不同于SOS的下游后果。这一信息是至关重要的，因为大多数颞下颌关节功能障碍（TMD）的概念都是将颞下颌关节视为包含典型关节软骨的滑膜关节。如果MCC中的软骨外周细胞与SUT中的细胞而不是SOS中的细胞具有相同的调节特征，这种假设不仅是错误的，而且可能导致不适当的治疗策略。