Characterization of osteoclast progenitors and their hormonal regulation in murine bone marrow

Date of Completion

January 2006

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Osteoclasts have the unique function of resorbing bone. Unlike the other cells that make up bone tissue, osteoclasts are of hematopoietic origin. Several studies have attempted to identify progenitor populations (OcPs) that are capable of generating osteoclasts. However, the available information has not led to a consensus regarding their identity and phenotype in the bone marrow (BM). Various cytokines and hormones influence osteoclast development and maturation in vivo and our inability to identify committed populations of OcPs has hindered the study of the dynamics of osteoclastogenesis in vivo. ^ In this body of work, we first dissected the osteoclast lineage pathway by defining its cellular component in murine BM. We characterized several fractions containing osteoclastogenic activity in vitro (chapter 3) and found that contrary to some previous reports, the osteoclastogenic activity of BM was concentrated in the CD45R-CD3-CD11b lowCD117+CD115high fraction and not the CD11bhigh fraction. We also observed that OcPs transiently upregulated CD11b expression and downregulated CD117 upon M-CSF stimulation. ^ Using this information, we evaluated the dynamics of osteoclastogenesis in relation to other hernatopoietic cells in vivo using two model systems where enhanced osteoclastogenicity was thought to be due to an increase in the numbers of OcPs. We used a model of osteoporosis induced by estrogen removal (chapter 4) and a model of intermittent PTH treatment (chapter 5). Interestingly, there was no increase in the total numbers of OcPs populations in either of these two models. On the contrary, we observed a decrease in the in vitro osteoclastogenicity of treated BM compared to that of control, and this correlated with a decrease in the absolute numbers of one or more OcPs populations. We propose that the decrease in OcPs observed in vivo might be due to the migration of late OcPs from the BM and/or an exhaustion of OcPs in the BM. ^ In summary, we have identified populations of OcPs and have provided new insights into the mechanism of action of estrogens and PTH. These studies will hopefully contribute to a better understanding of estrogen deficiency-induced osteoporosis and its treatment by PTH.^

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