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.

Public Health Relevance

Mice deficient in Pax5, a transcription factor required for B cell differentiation, lose 65% of their bone mass due to markedly increased osteoclastogenesis. We have been able to isolate and characterize an adherent cell population from the spleen of Pax5-/- mice that secretes a novel cytokine that induces wild-type bone marrow cell proliferation and primes those cells to become osteoclast precursors. Identification of this cytokine may reveal a novel pathway that regulates myeloid cell differentiation and the bone loss associated with inflammatory diseases like rheumatoid arthritis, periodontal disease and prosthetic implant failure.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR063787-02
Application #
8692538
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510