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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：
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
项目类别：
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

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）：骨髓是成骨细胞、造血细胞和免疫细胞的来源。破骨细胞与巨噬细胞、粒细胞和树突状细胞一样，都是源自造血干细胞的髓系细胞。早期造血细胞分化为多潜能祖细胞