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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ(-/-) mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.
"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 . Moreover, the expression of SOST/sclerostin, a Wnt inhibitor and suppressor of osteoblast proliferation and functions, was increased significantly in these mice. "
[Show abstract][Hide abstract] ABSTRACT: The last decade has seen an exponential increase in our understanding of osteocytes function and biology. These cells, once considered inert by-standers trapped into the mineralized bone, has now risen to be key regulators of skeletal metabolism, mineral homeostasis, and hematopoiesis. As tools and techniques to study osteocytes improved and expanded, it has become evident that there is more to these cells than initially thought. Osteocytes are now recognized not only as the key responders to mechanical forces but also as orchestrators of bone remodeling and mineral homeostasis. These cells are the primary source of several important proteins, such as sclerostin and fibroblast growth factor 23, that are currently target as novel therapies for bone loss (as the case for antisclerostin antibodies) or phosphate disorders. Better understanding of the intricate cellular and molecular mechanisms that govern osteocyte biology will open new avenue of research and ultimately indentify novel therapeutics to treat bone and mineral disorders. This review summarizes novel findings and discusses future avenues of research.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.