Myeloid Lineage Differentiation and Osteoclast Priming by a Novel Pax5 Cytokine

新型 Pax5 细胞因子的骨髓谱系分化和破骨细胞启动

基本信息

批准号：
8692538
负责人：
MARK C HOROWITZ
金额：
$ 17.69万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692538
关键词：
Animals B cell differentiation B-Lymphocytes Bone Marrow Bone Marrow Cells Cell Differentiation process Cell Line Cell Lineage Cell Proliferation Cells Cessation of life Conditioned Culture Media Data Databases Dendritic Cells Development Digestion Disease Failure Genes Goals Growth Factor Hematopoietic Hematopoietic stem cells Immune Implant Inflammatory Liquid Chromatography Maintenance Mature B-Lymphocyte Mus Myelogenous Myeloid Cells Myeloid Progenitor Cells Osteoclasts Pathway interactions Performance Periodontal Diseases Phase Phenotype Play Population Prosthesis Proteins Regulation Repression Rheumatoid Arthritis Role Science Series Source Spleen Staging Stem cells TCF3 gene bone bone cell bone loss bone mass cell type cytokine derepression experience granulocyte macrophage member novel osteoclastogenesis osteogenic premature progenitor public health relevance substantia spongiosa transcription factor

项目摘要

DESCRIPTION (provided by applicant): Bone marrow is the source of osteogenic, hematopoietic, and immune cells. It is now well accepted that osteoclasts, like macrophages, granulocytes and dendritic cells, are members of the myeloid lineage arising from hematopoietic stem cells. During the early stages of hematopoietic cell differentiation multipotential progenitor (MPP) cells can give rise to either myeloid progenitors or B lymphocyte progenitors. These early cell fate decisions are regulated, in part, by the expression or repression of proteins under the control of a series of transcription factors (TFs), which include, PU.1, Ikaros, E2A, Ebf1, Pax5 and Gon4-like. With the exception of PU.1 and Ikaros the other TFs are most often associated with B cell differentiation. However, we and others have shown that some of these TFs play an important role in bone cell development. How these TFs regulate the early cell fate choice between osteoclast and B cell differentiation is however only starting to be explored but with little direct data available. This regulation takes on added significance because of data showing that immune cells can be potent regulators of osteoclast differentiation. We have begun an analysis of mice deficient in Pax5, a TF required for commitment and maintenance of the B cell lineage. These animals experience a developmental block in B cell differentiation resulting in a phenotype characterized by the absence of most B cells. Importantly, these mice are also severely runted; they develop strikingly decreased trabecular bone mass with markedly increased numbers of osteoclasts. We have been able to isolate and characterize an adherent cell population from the spleen of Pax5-/- mice that grows continuously in culture without added growth factors and can give rise to osteoclasts, macrophages and dendritic cells. In addition, these cells secrete a cytokine(s) that induces proliferation and primes wild-type cells to also become myeloid progenitor cells. It is our hypothesis that the loss of Pax5 leads to the derepression of specific genes that allow the secretion of this novel cytokine(s), which induces myeloid progenitor cell differentiation resulting in increased osteoclastogenesis and this in turn produces the resultant bone phenotype. In broader terms, loss of Pax5 may have revealed a new pathway that regulates myeloid cell differentiation and specifically osteoclasts. The goal of this proposal is to identify that cytokine(s) and thus the mechanism(s) by which Pax5 regulates myeloid cell differentiation.

描述（由申请人提供）：骨髓是成骨，造血和免疫细胞的来源。现在可以很好地接受的是，巨噬细胞，粒细胞和树突状细胞等破骨细胞是由造血干细胞引起的髓样谱系的成员。在造血细胞分化多能祖细胞的早期阶段（MPP）细胞可以引起髓样祖细胞或B淋巴细胞祖细胞。这些早期的细胞命运决定部分通过在一系列转录因子（TFS）的控制下的表达或抑制来调节，其中包括PU.1，Ikaros，E2A，E2A，EBF1，PAX5，PAX5和GON4样。除了PU.1和Ikaros外，其他TF通常与B细胞分化有关。但是，我们和其他人表明，其中一些TF在骨细胞发育中起着重要作用。然而，这些TF如何调节破骨细胞和B细胞分化之间的早期细胞命运选择才被开始探索，但几乎没有直接数据可用。由于数据表明免疫细胞可以是破骨细胞分化的有效调节剂，因此该调节具有附加意义。我们已经开始对缺乏PAX5的小鼠进行分析，PAX5是B细胞谱系的承诺和维持所需的TF。这些动物在B细胞分化中经历了发育障碍，导致表型，其特征是大多数B细胞的缺乏。重要的是，这些小鼠也被严重运行。他们随着破骨细胞数量的明显增加而产生的小梁骨量显着降低。我们已经能够与Pax5 - / - 小鼠的脾脏中的粘附细胞群隔离并表征，这些细胞群在培养中不断生长而没有增加生长因子，并可能引起破骨细胞，巨噬细胞和树突状细胞。此外，这些细胞分泌一种细胞因子，该细胞因子诱导增殖和素型野生型细胞也成为髓样祖细胞。我们的假设是，PAX5的丧失导致了特定基因的压抑，该基因允许这种新型细胞因子的分泌，从而诱导髓样祖细胞分化，从而导致骨质造成骨质发生的增加，并且这会产生所得的骨骼表型。从更广泛的角度来看，PAX5的丧失可能揭示了一种调节髓样细胞分化，特别是破骨细胞的新途径。该建议的目的是确定细胞因子，从而确定PAX5调节髓样细胞分化的机制。