Regulation of Mandibular Condylar Cartialage Growth

描述(申请人提供)：本申请的长期目标是更好地了解下颌骨髁状突软骨(MCC)的增殖和生长是如何调节的，以及它是否与肢体初级软骨(生长板)的生长不同。这一认识可以被用来设计出更好的治疗策略来治疗颞颌关节的生长问题和持续性炎症性疾病。对于颅缝、下颌骨髁状突软骨和颅底软骨生长的分子决定因素有何不同，我们知之甚少。最近的研究提供了线索，表明MCC的增殖调控可能更类似于颅缝，而不是四肢软骨。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。我们推测，下颌突软骨的软骨前体细胞和颅缝的骨祖细胞具有共同的调控分子和受体，不同于原始软骨的增殖软骨细胞。这一假设将通过三个特定的目标得到验证：1)在组织块培养中，建立成纤维细胞生长因子-2和转化生长因子-β2活性的下游介质(Twist和Dachl)在MCC、颅缝(SUT)和蝶枕骨联合软骨(SOS)的初级软骨中的定位。我们将检验假设，即FGF2和转化生长因子-β2在MCC和SUT中的活性调节因子是相同的，而在SOS中它们与FGF2和转化生长因子-β2活性的调节因子不同；2)从MCC、SUT和SOS外植体中去除骨膜是增强还是抑制Twist或Dach1的表达。我们将验证这样的假设，即骨膜产生的因子在MCC、SUT和SOS中以不同的方式调节Twist和Dachl的表达和活性；3)在适当的基因敲除小鼠品系中测试外植体研究的结果。我们将检验这样一个假设，即体内FGF2或转化生长因子-β2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，因为大多数关于颞下颌关节功能障碍(TMD)的概念都将TMJ视为包含典型关节软骨的滑膜关节。如果MCC中的软骨膜细胞与SUT而不是SOS中的细胞具有共同的调控特征，这一假设不仅是错误的，而且可能导致不适当的治疗策略。

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.