Intercellular Communication in Paget's Disease of Bone

佩吉特骨病的细胞间通讯

• 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
• 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

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 成骨细胞（OB）和破骨细胞（OC）在骨重建过程中相互作用密切相关， 协调一致。佩吉特骨疾病（PDB）是一种局灶性疾病，其中这种协调活动已经被破坏。 导致骨骼重塑过度作为第二大最常见的代谢性骨病， 骨质疏松症，它影响1-3%的50岁以后的美国人口。PDB是一种遗传异质性疾病， 然而，有两个强有力的关联与PDB有关：Sequestosome 1（SQSTM 1）基因突变 在家族性和体细胞性PDB中发现，研究将PDB与麻疹的存在联系起来 病毒核衣壳蛋白（MVNP）。PDB的病因学研究主要集中在破骨细胞 然而，当我们检查疾病的躯体形式时，我们的数据表明， pagetic OB和pagetic OC之间涉及趋化因子的正反馈环信号通路 信号分子CCL 5、CXCL 6和它们各自的受体CCR 5和CXCR 1，我们假设它们是 是导致这种疾病的原因我们发现这些趋化因子信号的变化涉及OB 携带SQSTM 1 mut和表达MVNP的OC。我们还发现，表达MVNP的OC强烈地 上调了一种趋化因子，吸引OB和前OC细胞。此外，我们发现，并不是所有的OB细胞中， PDB病变携带SQSTM 1突变，表明PDB病变由复杂的嵌合体组成， OB细胞类型，其中只有一个亚群携带SQSTM 1突变，验证了募集生长 假说.为了验证这一点，我们提出了三个具体目标。目的1比较pagetic OC的基因组表达， 来自具有和不具有SQSTM 1突变以及具有和不具有MVNP表达的PDB。目标2将测试是否 表达MVNP的前OC细胞优先响应来自表达SQSTM 1 mut的OB的信号而迁移。 混合实验将使用具有或不具有SQSTM 1突变的OB和具有或不具有MVNP的前OC 表达以检查引导迁移和吸引的趋化因子信号。目标3将测试自放大 涉及MVNP表达OC细胞放大化学引诱物信号的正反馈回路模型 由携带SQSTM 1 mut-OB发起。总之，这种范式转变的研究将促进对 OB和OC在骨重建和疾病过程中的相互作用，并可能开辟新的方法， PDB处理仅靶向突变体OB和OC细胞。