CRANIAL VS APPENDICULAR SKELETAL REPAIR MECHANISMS

骨骼发育需要细胞特化、迁移、增殖和分化程序的精密协调，这些程序由组织层和细胞外基质之间的相互作用调节。许多相同的事件发生在成人骨修复过程中。然而，目前还不清楚骨骼愈合过程在多大程度上是骨骼发育过程的重演。本研究的目的是阐明调节颅骨骨骼修复的分子和细胞机制，重点是下颌骨。基本假设是成人组织通过使用胎儿骨骼生成程序愈合。提出了以下具体目标。(1)通过组织学和分子生物学方法确定颅骨骨骼中关键软骨细胞和成骨细胞特异性基因产物的时空分布。(2)确定下颌骨修复的调控机制。在这个目标中，骨骼将被允许通过主要意图（膜内骨化）愈合，并且似乎调节颅骨骼组织的分子的表达和功能将被扰乱。(3)通过遗传学和生物化学方法确定骨发育紊乱对颅骨骨骼组织的影响。明胶酶-B敲除小鼠将用于研究明胶酶B在下颌骨形成中的调节作用。明胶酶B小鼠由于血管生成延迟而具有生长板骨化的异常模式。这些实验将评估下颌骨形态发生和长骨发育之间的相似性和差异。这些研究可能揭示颅骨骨骼组织的形成和修复之间，或颅骨骨骼组织和长骨的修复之间的根本差异。长期目标是利用这些信息开发基于生物学的治疗方法，用于治疗由创伤和疾病引起的骨骼畸形和缺陷。

Skeletal development requires an exquisite coordination of programs for cell specification, migration, proliferation and differentiation that are regulated by interactions between tissue layers and the extracellular matrix. Many of the same events occur during adult bone repair. However, it is unclear to what extent the process of skeletal healing is a recapitulation of the skeletal development program. The goal of this research is to elucidate the molecular and cellular mechanisms regulating cranial skeletal repair, with a focus on the mandible. The underlying hypothesis is that adult tissues heal by using the fetal skeletogenic program. The following specific aims are propose. (1) Determine the spatial and temporal distribution of key chondrocyte- and osteoblast-specific gene products in the cranial skeleton by histological and molecular means. (2) Determine the mechanisms regulation repair in the mandible. In this aim, bones will be allowed to heal by primary intention (intramembranous ossification), and the expressions and functions of molecules that appear to regulate cranial skeletal tissues will be perturbed. (3) Determine the effects on cranial skeletal tissues of perturbing bone development by genetic and biochemical means. The gelatinase-B null mouse will be used to study the role of gelatinase B in regulation of mandibular bone formation. Gelatinase B mice have abnormal pattern of growth plate ossification due to a delay in angiogenesis. These experiments will assess similarities and differences between mandibular morphogenesis and long bone development. These studies may uncover fundamental differences between formation and repair of cranial skeletal tissues, or between the repair of cranial skeletal tissues and long bones. The long term goal is to use this information to develop biologically based therapies for the treatments of skeletal deformities and defects cause by trauma and disease.