Characterization of OGFRL1 Knockout Mice

对罕见疾病的研究提供了对正常人类生理学的见解，并导致了一些策略， 预防和治疗常见疾病。巨颌症（OMIM#118400）是一种常染色体显性形式的纤维性 颌骨发育不良，其特征是由纤维性骨破坏引起的上颌骨和下颌骨破坏， 炎性病变目前，SH 3结构域结合蛋白2（SH 3BP 2）是唯一负责 天真无邪然而，我们已经确定了新的常染色体隐性长胖症患者谁没有 在叙利亚和印度的近亲家庭中发现SH 3BP 2突变。为了识别新的天使基因，我们 进行了全外显子组测序，发现了阿片样物质中的纯合功能丧失突变。 受影响成员的生长因子受体样1（OGFRL 1）基因。初步结果表明 OGFRL 1-敲低增加了细胞对增加TNF-α产生的敏感性， 单核细胞/巨噬细胞系RAW 264.7。敲低的RAW 264.7细胞也显示出增加的 对核因子-κ B配体（RANKL）的受体激活剂的反应性，导致增加 破骨细胞的形成。因此，我们认为OGFRL 1是一种新的巨噬细胞负调节因子， 活化和破骨细胞分化来调节骨丢失的易感性。我们的总体假设是 OGFRL 1的功能丧失是隐性长胖症的原因，OGFRL 1还没有 调节骨量的未知功能。具体目的是：目的1）确定OGFRL 1敲除是否 小鼠再现了具有OGFRL 1突变的人的表型。目的2）确定OGFRL 1是否 调节牙周炎模型中的骨丢失。目的3）确定OGFRL 1是否调节骨丢失， 类风湿性关节炎模型。我们将确定OGFRL 1作为一个新的基因负责cherubism和探索 OGFRL 1是否是常见炎性骨病中骨吸收的新调节因子。这些研究 将为巨像症的病因学提供新的见解，并确定治疗巨像症的新途径。 牙周病和类风湿性关节炎。

The study of rare diseases has provided insights into normal human physiology and has led to strategies to prevent and treat common diseases. Cherubism (OMIM#118400) is an autosomal dominant form of fibrous dysplasia of the jaws characterized by maxillary and mandibular bone destruction caused by fibrous- inflammatory lesions. Currently, SH3-domain binding protein 2 (SH3BP2) is the only gene responsible for cherubism. However, we have identified new autosomal recessive cherubism patients who do not have mutations in SH3BP2 in consanguineous families from Syria and India. To identify novel cherubism genes, we performed whole exome sequencing and discovered homozygous loss-of-function mutations in the opioid growth factor receptor-like 1 (OGFRL1) gene of the affected members. Preliminary results showed that OGFRL1-knockdown increases cellular sensitivity to increase TNF-alpha production in a monocyte/macrophage cell line RAW264.7. The knockdown RAW264.7 cells also showed increased responsiveness to the receptor activator of nuclear factor-kappa B ligand (RANKL), resulting in increased formation of osteoclasts. Therefore, we propose that OGFRL1 is a novel negative regulator of macrophage activation and osteoclast differentiation to regulate the susceptibility to bone loss. Our overall hypothesis is that loss-of-function of OGFRL1 is responsible for a recessive form of cherubism and that OGFRL1 has yet unknown functions in regulating bone mass. Specific aims are: Aim 1) Determine whether OGFRL1 knockout mice recapitulate the phenotype of humans with OGFRL1 mutations. Aim 2) Determine whether OGFRL1 regulates bone loss in a periodontitis model. Aim 3) Determine whether OGFRL1 regulates bone loss in a rheumatoid arthritis model. We will establish OGFRL1 as a new gene responsible for cherubism and explore whether OGFRL1 is a new regulator of bone resorption in common inflammatory bone diseases. These studies will provide new insights into the etiology of cherubism and identify new pathways for the treatment of periodontal diseases and rheumatoid arthritis.