Characterization of OGFRL1 Knockout Mice

对罕见疾病的研究提供了对正常人类生理的洞察，并导致了战略 防治常见病。切尔鲁比症(OMIM#118400)是一种常染色体显性纤维性遗传病 颌骨发育不良的特征是由纤维性骨病引起的上颌骨和下颌骨的破坏。 炎症性病变。目前，SH3结构域结合蛋白2(SH3BP2)是唯一负责 小天使主义。然而，我们发现了新的常染色体隐性遗传性小天使症患者，他们没有 来自叙利亚和印度的近亲家庭SH3BP2基因突变。为了鉴定新的小天使主义基因，我们 进行了完整的外显子组测序，发现了阿片类药物的纯合子功能丧失突变 受影响成员的生长因子受体样1(OGFRL1)基因。初步结果显示， OGFRL1-基因敲除增加细胞敏感性以增加肿瘤坏死因子-α的产生 单核/巨噬细胞系RAW264.7。被敲除的RAW264.7细胞也表现出增加 对核因子-kappa B受体激活剂配体(RANKL)的反应性，导致 破骨细胞的形成。因此，我们认为OGFRL1是一种新的巨噬细胞负性调节因子 激活和破骨细胞分化，以调节对骨丢失的敏感性。我们的总体假设是 OGFRL1的功能丧失是隐性的小天使症的原因，而OGFRL1至今 调节骨量的功能未知。具体目标是：目标1)确定OGFRL1基因是否被敲除 小鼠重现了带有OGFRL1突变的人类的表型。目的2)确定OGFRL1是否 在牙周炎模型中调节骨丢失。目的3)确定OGFRL1是否调节骨丢失。 类风湿性关节炎模型。我们将建立OGFRL1作为与小天使症有关的新基因，并探索 OGFRL1是否是常见炎症性骨病骨吸收的新调节因子。这些研究 将为小天使症的病因学提供新的见解，并确定新的治疗途径 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.