CDC73基因异常在颌骨骨化纤维瘤发病中的作用

The benign fibro-osseous lesions (BFOL) represent a clinically diverse group of disorders of bone that share similar histologic features and are relatively common in the jaws. BFOL include lesions of different nature such as developmental lesions, reactive or dysplastic processes, and neoplasms. Ossifying fibroma(OF), fibrous dysplasia(FD) and osseous dysplasia(OD) are the most common forms of BFOL. As they show distinct patterns of disease progression, it is important to distinguish them. OF need to be completely enucleated from the surrounding bone due to its risk for recurrence. On the contrary, The growth of FD usually tends to stabilize when skeletal maturity is attained. Therefore, surgical intervention is usually only used for cosmetic or functional purpose. However, these lesions often present a diagnostic dilemma because of uncertainties concerning the diagnostic significance of specific radiological and histological features; especially in biopsy specimen, therefore, accurate diagnosis of these lesions can be difficult. So it is important to research the mechanism of OF. Hyperparathyroidism-jaw tumor (HPT-JT) syndrome The HPT-JT locus was mapped to chromosome 1q25-q31 and the putative gene designated hyperparathyroidism type 2 (HRPT2), recently named as CDC73, encodes a 531 amino acid protein called parafibromin. The prevalence and range of CDC73 mutations and function in sporadic OF remain to be established, in view of the limited number of cases examined to date. The present study intend to :1.Separated and identified mesenchymal stem cells from ossifying fibroma (MSC-OF) which canbe used as disease model in future study, capable of generating OF-like lesion when transplanted into immunocompromised mice. 2. To establish the prevalence and range of CDC73 mutations and LOH in sporadic OF by DNA sequencing, gene scan, PCR, et al.3.The effect of abnomal expression of parafibromin on MSC-OF in osteoblast differentiation.

对颌骨骨化纤维瘤（OF）发病机制进行研究将利于对颌骨发育、致病机理的理解，并具有重要的临床意义。CDC73基因已被确定为甲状旁腺功能亢进-颌骨肿瘤综合征的致病基因，但其与更为常见的不伴综合症的颌骨OF的关系并不清楚。本研究1.分离鉴定OF的间充质干细胞，建立裸鼠皮下OF体内模型，为OF的发病机制研究提供良好的工具；2.用基因测序、基因扫描、甲基化PCR、免疫组化、RT-PCR、Western等方法从基因、mRNA、蛋白水平研究CDC73基因异常在颌骨OF中的分布及频率；3.利用分离鉴定好的OF间充质干细胞，用MTT、BrdU掺入、克隆形成、流式细胞周期分析、免疫组化、RT-PCR、Western、基因克隆、SiRNA、pTOPFLASH等方法研究CDC73基因异常所导致的其编码的蛋白parafibromin功能异常对OF间充质干细胞增殖及成骨分化的影响，探索OF的发病机制。

颌骨骨化纤维瘤（Ossifying Fibroma，OF）是一种好发于青少年，边界清楚，由富于细胞的纤维组织和形态异常的矿化组织构成的颌骨病变，目前发病机制尚不清楚。OF属于颌骨骨纤维性病变(fibro-osseous lesions, FOL)。颌骨FOL包括的纤维异常增殖症(fibrous dysplasia, FD)、骨异常增殖症(osseous dysplasia, OD)及OF。它们的组织学表现相似，均表现为正常的颌骨组织被富含纤维组织的异常骨组织取代，均是由于成骨细胞发生了异常的增殖分化所致。不同的病因导致颌骨相似的病理改变,对FOL病变的分子机制的研究，将有利于理解不同的致病因素、调控机制对颌骨骨发育影响，对FOL病变形态形成的作用。。在临床实践中存在大量临床、病理、放射学特点相互重叠的病例，要将某一具体的纤维骨病变与其它病变相区别仍存在问题，特别是早期病例及活检病例。FOL的治疗依赖于最后的诊断，诊断不同，治疗方法完全不同。对颌骨骨化纤维瘤（OF）发病机制进行研究将利于对颌骨发育、致病机理的理解，并具有重要的临床意义。CDC73基因已被确定为甲状旁腺功能亢进-颌骨肿瘤综合征的致病基因，但其与更为常见的不伴综合症的颌骨OF的关系并不清楚。本研究1.成功分离鉴定OF的间充质干细胞，建立了裸鼠皮下OF体内模型，为OF的发病机制研究提供良好的工具；2.用基因测序、基因扫描、免疫组化、RT-PCR等方法从基因、mRNA、蛋白水平研究CDC73基因异常在颌骨OF中的分布及频率，发现在40例散发性OF中，2例有体细胞水平的突变，均位于1号外显子，均未出现杂合性缺失。在不伴综合征的多发性病变中，未见基因突变。但伴CDC73基因异常的病例其编码的蛋白parafibromin的表达、功能没有明显的异常。说明CDC73基因的异常仅在少部分散发性颌骨骨化纤维瘤发病中起作用。