Intercellular Communication in Paget's Disease of Bone

佩吉特骨病的细胞间通讯

基本信息

批准号：
10425439
负责人：
MARC F HANSEN
金额：
$ 17.86万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425439
关键词：
Adverse effects Affect Age Area Atrial Fibrillation Binding Bone Diseases Bone Pain Bone necrosis Bone remodeling CCL5 gene CCR5 gene CXCL5 gene CXCL6 gene Cell Line Cells Chemotactic Factors Chronic Communication Complex Data Databases Deformity Disease Etiology Event Feedback Femoral Fractures Fostering Frequencies Genes Genetic Genetic Heterogeneity Genomics Growth Human IL8RA gene In Vitro Inherited Investigation Jaw Lead Lesion Ligands Link Measles virus nucleocapsid protein Metabolic Bone Diseases Minority Modeling Mosaicism Mutation Osteitis Deformans Osteoblasts Osteoclasts Osteoporosis Pathological fracture Patients Persons Population Predisposition RANTES Research Risk Role Signal Pathway Signal Transduction Signaling Molecule Site Somatic Mutation Testing Up-Regulation bisphosphonate bone bone turnover cell type chemokine chemokine receptor experimental study gastrointestinal intercellular communication laser capture microdissection middle age migration mutant novel novel strategies osteosarcoma protein expression receptor recruit response side effect

项目摘要

Project Summary The interactions of osteoblasts (OB) and osteoclasts (OC) during bone remodeling are connected and highly coordinated. Paget’s Disease of Bone (PDB) is a focal disease in which this coordinated activity has been disrupted leading to exaggerated bone remodeling. As the second most common metabolic bone disease after osteoporosis, it affects 1-3% of the U.S. population after age 50. PDB is a genetically heterogeneous disease, however two strong associations have been linked to PDB: mutations in the Sequestosome 1 (SQSTM1) gene have been found in familial and somatic PDB and studies have linked PDB with the presence of the measles virus nucleocapsid protein (MVNP). Studies of the etiology of PDB has largely focused on osteoclast dysregulation, however, when we examined the somatic form of the disease, our data suggest a self-amplifying positive feedback loop signaling pathway between the pagetic OB and pagetic OC involving the chemokine signaling molecules CCL5, CXCL6 and their respective receptors CCR5 and CXCR1 that we hypothesize is responsible for the etiology of this disease. We found that these changes in chemokine signaling involved OBs carrying a SQSTM1mut and OCs expressing MVNP. We also found that MVNP-expressing OCs strongly upregulated a chemokine that attracts OB and pre-OC cells. Moreover, we found that not all the OB cells in the PDB lesion carried the SQSTM1 mutation suggesting that PDB lesions are composed of a complex mosaic of OB cell types, in which only a subset carry the SQSTM1 mutation validating the growth-by-recruitment hypothesis. To test this, we propose three specific aims. Aim 1 will compare genomic expression of pagetic OC from PDB with and without a SQSTM1 mutation and with and without MVNP expression. Aim 2 will test whether MVNP-expressing pre-OC cells preferentially migrate in response to signals from SQSTM1mut-expressing OB. Mixing experiments will use OB with or without a SQSTM1 mutation and pre-OC with or without MVNP expression to examine chemokine signals directing migration and attraction. Aim 3 will test for a self-amplifying positive feedback loop model involving MVNP-expressing OC cells amplifying the chemoattractant signals initiated by SQSTM1mut-carrying OB. Together, this paradigm-shifting research will foster new understanding of interactions between OB and OC during bone remodeling and disease and potentially open new approaches to PDB treatment that target only the mutant OB and OC cells.

项目摘要骨重塑过程中成骨细胞（OB）和破骨细胞（OC）的相互作用连接起来，高度协调。 Paget的骨骼疾病（PDB）是一种局灶性疾病，这种协调活性一直是破坏导致夸张的骨头重塑。作为第二个最常见的代谢骨病骨质疏松症，它影响50岁以后美国人群的1-3％。PDB是一种遗传异质性疾病，但是，两个强大的关联已与PDB相关联：Secestosome 1（SQSTM1）基因中的突变在家族和体细胞PDB中发现，研究已将PDB与麻疹的存在联系起来病毒核苷蛋白（MVNP）。 PDB病因的研究主要集中在破骨细胞上但是，当我们检查疾病的躯体形式时，我们的数据表明自我扩大涉及趋化因子的Pagetic OB和Pagetic OC之间的正反馈回路信号传导途径我们假设的信号分子CCL5，CXCL6及其各自的受体CCR5和CXCR1是负责这种疾病的病因。我们发现趋化因子信号传导的这些变化涉及ABS 携带表达MVNP的SQSTM1MUT和OCS。我们还发现表达MVNP的OC强烈上调吸引OB和OC前细胞的趋化因子。此外，我们发现并非所有的OB细胞 PDB病变带有SQSTM1突变，表明PDB病变由复杂的镶嵌物组成 OB细胞类型，其中只有子集携带SQSTM1突变，以验证逐渐增长假设。为了测试这一点，我们提出了三个具体目标。 AIM 1将比较Pagetic OC的基因组表达从具有和不具有SQSTM1突变的PDB以及没有MVNP表达的PDB。 AIM 2将测试是否表达MVNP的OC前细胞优先响应于SQSTM1MUT表达OB的信号。混合实验将使用或不带有SQSTM1突变的OB，并在有或没有MVNP的情况下使用OB 表达指导迁移和吸引力的趋化因子信号。 AIM 3将测试自我扩增涉及表达MVNP的OC细胞的正反馈回路模型放大了趋化剂信号由SQSTM1MUT携带OB发起。这项范式转移研究将共同促进对骨骼重塑和疾病期间OB和OC之间的相互作用，并有可能打开新方法 PDB治疗仅针对突变OB和OC细胞。