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The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO |
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| Authors: | Rankin Erinn B Wu Colleen Khatri Richa Wilson Tremika L S Andersen Rebecca Araldi Elisa Rankin Andrew L Yuan Jenny Kuo Calvin J Schipani Ernestina Giaccia Amato J |
| Institution: | 1 Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94303-5152, USA 2 Division of Hematology, Stanford University, Stanford, CA 94303-5152, USA 3 Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, MA 02114, USA 4 Inflammation and Immunology, Pfizer, Cambridge, MA 02140, USA |
| Abstract: | Osteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment. |
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