Myelopoiesis is regulated by osteocytes through Gs -dependent signaling

Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
Blood (Impact Factor: 10.45). 11/2012; 121(6). DOI: 10.1182/blood-2012-06-437160
Source: PubMed


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.

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Available from: Roland Baron, Nov 19, 2015
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    • "Both G-CSF and TNFa are commonly upregulated upon TLRmediated stimulation during emergency granulopoiesis and after infections (Hirai et al., 2006; Ueda et al., 2005). Their increased expression is also a common feature of several animal models of myeloproliferative-like disease (Dumortier et al., 2010; Fulzele et al., 2013; Walkley et al., 2007; Yoda et al., 2011) and it is observed in patients with MPN (Tefferi et al., 2011). Our discovery of the Notch/miR-155/NF-kB/cytokines axis suggests the hypothesis that Notch signaling may contribute to hematopoietic homeostasis by regulating the level of the inflammatory state in the BM niche. "
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    • "Using a novel ex vivo coculture system using osteocyte-enriched bone explants we identified granulocyte colony-stimulating factor as the principal cytokine regulating granulopoiesis in these mice. Interestingly, PTH1R signaling in osteocytes is not responsible for the myeloproliferative phenotype since mice lacking receptor expression in osteocytes (Ocy-PPRKO) have normal hematopoiesis [45]. Moreover, the expression of SOST/sclerostin, a Wnt inhibitor and suppressor of osteoblast proliferation and functions, was increased significantly in these mice. "
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