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

• 批准号: 8581522
• 负责人: MARK C HOROWITZ
• 金额: $ 21.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581522
• 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

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）：骨髓是成骨细胞、造血细胞和免疫细胞的来源。现在公认的是，破骨细胞，如巨噬细胞，粒细胞和树突状细胞，是从造血干细胞产生的骨髓谱系的成员。在造血细胞分化的早期阶段， (MPP)细胞可以产生髓样祖细胞或B淋巴细胞祖细胞。这些早期细胞命运决定部分地通过在一系列转录因子（TF）控制下的蛋白质的表达或抑制来调节，所述转录因子包括PU.1、Ikaros、E2 A、Ebf 1、Pax 5和Gon 4样。除PU.1和Ikaros外，其他TF最常与B细胞分化相关。然而，我们和其他人已经表明，这些TF中的一些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刚刚开始探索，但几乎没有直接数据可用。这种调节具有额外的意义，因为数据显示免疫细胞可以是破骨细胞分化的有效调节剂。我们已经开始对Pax 5缺陷的小鼠进行分析，Pax 5是B细胞谱系定型和维持所需的TF。这些动物经历B细胞分化的发育阻滞，导致以大多数B细胞缺失为特征的表型。重要的是，这些小鼠也严重矮小;它们的骨小梁质量显著降低，破骨细胞数量显著增加。我们已经能够从Pax 5-/-小鼠的脾脏中分离和表征贴壁细胞群体，其在没有添加生长因子的情况下在培养物中连续生长，并且可以产生破骨细胞、巨噬细胞和树突状细胞。此外，这些细胞分泌细胞因子，其诱导增殖并引发野生型细胞也成为骨髓祖细胞。我们的假设是Pax 5的缺失导致特定基因的去抑制，这些基因允许这种新型细胞因子的分泌，其诱导髓样祖细胞分化，导致破骨细胞生成增加，这反过来又产生了所得的骨表型。从广义上讲，Pax 5的缺失可能揭示了一种新的调节髓系细胞分化的途径，特别是破骨细胞。该提议的目标是鉴定细胞因子，从而鉴定Pax 5调节髓样细胞分化的机制。