颌面部骨骼疾病十型胶原蛋白基因的异常调控

The craniofacial skeleton usually develops through an intramembranous pathway in which mesenchymal cells directly differentiate into osteoblasts. The long bone development is though an endochondral pathway which requires a cartilage intermediate. Deficiency of intramembranous pathway results in many craniofacial skeletal anomalies. These craniofacial syndromes constitute a large group of congenital skeletal disorders that account for most of the skeletal birth defects. The clinical severity of these craniofacial syndromes ranges from minor handicap to death in neonatal period. Noticeably, many craniofacial skeletal disorders are accompanied by long bone abnormalities. There is also evidence that periosteal cells of craniofacial bones undergo chondrogenic differentiation. These observations strongly suggest that the endochondral pathway plays an important role in pathological occurrence of craniofacial skeletal diseases. .However, until now, the mechanism by which the endochondral pathway causes craniofacial skeletal syndromes remains largely unknown. In this application, based on our series of research on Runx2 and Col10a1 (collagen X, alpha 1) genes, we propose that abnormal Col10a1 expression regulated by Runx2 constitutes a mechanistic basis of craniofacial skeletal disease. Both Runx2 and Col10a1 genes are known to play important function in chondrocyte maturation during endochondral ossification. Characterizing the correlation of Runx2 dysregulated Col10a1 expression with craniofacial skeletal diseases will facilitate identification of novel therapeutic targets for these diseases showing abnormal Col10a1 expression and chondrocyte maturation.

颌面部骨骼发育通常是通过间质细胞直接分化为骨细胞这一膜内成骨的方式进行。长骨或四肢骨干的发育则是以软骨细胞分化成熟即软骨内成骨的模式进行。膜内成骨受损可致多种颌面部骨骼畸变，占骨骼系统遗传病和出生缺陷的多数。临床表现为功能障碍或直接导致新生儿死亡。此外，许多颌面部综合症伴有长骨骨骼异常，现有资料也显示颌面部骨质细胞具有软骨细胞分化的属性，这些观察强烈提示软骨内成骨在颌面部骨骼疾病发生中起重要作用。然而，软骨内成骨如何参与颌面部骨骼疾病的发生迄今仍不清楚。基于长期对转录因子Runx2 和十型胶原蛋白基因Col10a1的研究，我们提出Runx2对Col10a1基因的调控异常是导致该类疾病发生的重要的病理基础。已知Runx2 和Col10a1 基因是软骨成熟的关键因素。进一步阐明Runx2 对Col10a1 基因的病理性调控与颌面部骨骼疾病发生发展的关联性，对于靶向治疗这一临床疾病具有重要意义

十型胶原蛋白基因（COL10A1）在肥大型软骨细胞中特异表达，而软骨细胞肥大成熟是软骨内成骨发育的重要阶段。十型胶原蛋白基因（COL10A1）表达改变或软骨细胞异常肥大均可导致多种骨骼疾病，如身材矮小、骨盆畸形以及口腔颌面部骨骼异常等，表明个体的软骨内成骨和膜内成骨均受损。本项目通过研究小鼠十型胶原蛋白基因（Col10a1）的调控机制来阐明软骨内成骨与膜内成骨发育这两种骨骼发育重要途径的内在联系。为此，我们采用综合的生物信息学、蛋白质组学、分子细胞生物学以及小鼠遗传学等多种体内外研究手段，达到分离和鉴定多种小鼠Col10a1基因转录调节因子及辅因子的目的。 4年来， 我们成功地筛选了数十个小鼠Col10a1基因候选调节因子，如转录因子P63， Runx2， Sox9，Tbx5以及辅因子Cox-2的功能。我们还将上述因子与骨骼发育过程及多种相关骨骼疾病，包括躯干及颌面部骨骼异常、骨肿瘤以及骨关节炎等紧密联系。并建立了若干个含有报告基因和模拟人类骨骼疾病的动物模型。我们的研究成果分别发表在十数篇高质量的SCI期刊上(含1、2区期刊)。2014年作为突破性墙报被美国骨科年会收录。我们坚信这些研究成果将为进一步探讨相关骨骼病变的发病机理以及最终的精准医学防治提供重要的理论与实验依据和潜在的治疗靶点。