Intercellular Communication in Paget's Disease of Bone

项目摘要 成骨细胞(OB)和破骨细胞(OC)在骨重建过程中的相互作用是密切相关的 协调一致。帕吉特骨病(PDB)是一种局部疾病，在这种疾病中，这种协调活动一直 破坏导致夸张的骨骼重塑。仅次于第二常见的代谢性骨病 骨质疏松症，它影响1-3%的美国50岁以上的人口。帕金森病是一种遗传异质性疾病， 然而，有两个很强的关联与PDB有关：序列小体1(SQSTM1)基因的突变 已在家族性和躯体PDB中发现，研究已将PDB与麻疹的存在联系起来 病毒核蛋白(MVNP)。对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，我们的数据显示出一种自我放大的 Pagtic OB和Pagtic OC之间涉及趋化因子的正反馈环路信号通路 我们假设的信号分子CCL5、CXCL6及其各自的受体CCR5和CXCR1 对这种疾病的病原学负责。我们发现，趋化因子信号的这些变化与OB有关。 携带SQSTM1mut和表达MVNP的OCS。我们还发现MVNP强表达OCS 上调一种趋化因子，吸引去卵巢和去卵巢前细胞。此外，我们发现并不是所有的OB细胞都在 PDB病变携带SQSTM1突变，提示PDB病变由复杂的 OB细胞类型，其中只有一个子集携带SQSTM1突变，验证通过招募而生长 假设。为了检验这一点，我们提出了三个具体目标。目标1将比较Pagtic OC的基因组表达 在有和没有SQSTM1突变以及有和没有MVNP表达的情况下来自PDB。Aim 2将测试 表达MVNP的前OC细胞优先迁移来自表达SQSTM1mut的OB的信号。 混合实验将使用带有或不带有SQSTM1突变的OB和带有或不带有MVNP的前OC 检测指示迁移和吸引的趋化因子信号的表达。目标3将测试自我放大 表达MVNP的OC细胞放大趋化信号的正反馈回路模型 由携带SQSTM1mut的OB发起。总而言之，这种范式转换的研究将促进对 成骨细胞和成骨细胞在骨重建和疾病过程中的相互作用及其可能开辟的新途径 只针对突变的OB和OC细胞的PDB治疗。

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.