Role of the Parathyroid Hormone Receptor in Osteoblast Support of Erythropoiesis

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Project Summary Erythrocytes play a crucial role in the delivery of oxygen to meet the metabolic needs of tissues. Erythroid development occurs within the bone marrow, but when bleeding or erythrocyte destruction leads to a need for increased erythrocyte production (erythropoiesis), the spleen can become a secondary site for stress erythropoiesis. Within the bone marrow, the role of the osteoblast lineage in supporting hematopoietic stem cells and differentiation of hematopoietic lineages including B lymphocytes is now well established. Recent studies have expanded the contributions of the osteoblast lineage to the support of erythropoiesis as well, as osteoblasts are a potential source of the critical erythrocyte-regulating hormone erythropoietin (Epo). We have been interested in the role of signaling downstream of the parathyroid hormone receptor (PTH1R), a G protein- coupled receptor, in osteoblasts in regulating osteoblast support of erythropoiesis. In mice lacking PTH1R in the skeleton (PTH1R-OsxKO mice), we find a dramatic loss of erythrocytes in the spleen. The mechanisms that govern the migration of erythroid progenitors and erythroblasts from the bone marrow to the spleen in times of stress are largely undefined. Since these mice carry an osteoblast-specific deletion of PTH1R, the most likely model is that bone marrow erythropoiesis is sufficient at steady state, but unable to provide sufficient erythroid progenitors to the spleen during stress erythropoiesis. However, we find cells descended from osteoprogenitors in the spleen, therefore an impaired spleen environment in PTH1R-OsxKO mice may also be at work. Consistent with a defect in osteoblastic regulation of erythropoiesis, in preliminary studies we find a significant decrease in expression of Epo mRNA in bones of PTH1R-OsxKO mice. We hypothesize that PTH1R signaling in osteoblast progenitors regulates bone marrow erythroid development and trafficking to the spleen. In this proposal we will systematically analyze the following steps in PTH1R-OsxKO mice: 1) bone marrow commitment, differentiation and proliferation of erythroid progenitors and erythroblasts; 2) exit of marrow erythroblasts from the bone marrow to enter the peripheral circulation; 3) homing of circulating erythroid progenitors to the spleen, followed by engraftment and expansion within the splenic microenvironment. Together the accomplishment of the proposed studies will pinpoint the site(s) of dysregulation of spleen hematopoiesis in PTH1R-OsxKO mice, and may shed light upon the mechanisms that govern stress erythropoiesis as well as further clarifying a role for osteoblasts in the support of bone marrow erythropoiesis.