Abstract
Hematopoietic progenitors are regulated in their respective niches by cells of the bone marrow microenvironment. The bone marrow microenvironment is composed of a variety of cell types, and the relative contribution of each of these cells for hematopoietic lineage maintenance has remained largely unclear. Osteocytes, the most abundant yet least understood cells in bone, are thought to initiate adaptive bone remodeling responses via osteoblasts and osteoclasts. Here we report that these cells regulate hematopoiesis, constraining myelopoiesis through a Gsα-mediated mechanism that affects G-CSF production. Mice lacking Gsα in osteocytes showed a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. This hematopoietic phenomenon was neither intrinsic to the hematopoietic cells nor dependent on osteoblasts but was a consequence of an altered bone marrow microenvironment imposed by Gsα deficiency in osteocytes. Conditioned media from osteocyte-enriched bone explants significantly increased myeloid colony formation in vitro, which was blocked by G-CSF–neutralizing antibody, indicating a critical role of osteocyte-derived G-CSF in the myeloid expansion.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Bone Diseases, Metabolic / genetics
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Bone Diseases, Metabolic / metabolism
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Bone Marrow Cells / metabolism
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Cell Proliferation
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Cells, Cultured
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Cellular Microenvironment / genetics
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Female
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GTP-Binding Protein alpha Subunits, Gs / genetics
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GTP-Binding Protein alpha Subunits, Gs / metabolism*
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Gene Expression
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Granulocyte Colony-Stimulating Factor / genetics
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Granulocyte Colony-Stimulating Factor / metabolism
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins
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Male
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Mice
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Mice, Knockout
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Microscopy, Electron, Scanning
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Myeloid Cells / metabolism
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Myelopoiesis*
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Osteocytes / cytology
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Osteocytes / metabolism*
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Osteocytes / ultrastructure
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Receptor, Parathyroid Hormone, Type 1 / genetics
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Receptor, Parathyroid Hormone, Type 1 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Spleen / cytology
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Spleen / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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Receptor, Parathyroid Hormone, Type 1
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Sost protein, mouse
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Granulocyte Colony-Stimulating Factor
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GTP-Binding Protein alpha Subunits, Gs