Osteocytes link bone maintenance to blood homeostasis.

O steocytes are the most abundant cell type in the bone, comprising more than 90% of all cells within the bone matrix or on bone surfaces. Osteocytes are derived from osteoblasts and are entombed in the bone matrix during bone deposition. Osteocytes were originally thought to be rather inert cells whose function was limited to maintaining bone matrix locally. However, osteocytes are connected to other bone cells, endothelial cells, and hematopoietic cells near endosteal surfaces through an extensive network of canaliculi through which cytoplasmic projections of osteocytes travel. This network allows for the transport of proteins produced by osteocytes to act on cells in the bone marrow cavity. For example, osteocyte production of sclerostin and RANK ligand are key regulators of osteoblast and osteoclast activity, respectively (see figure).2,3 Because osteoblasts have been implicated in hematopoietic stem cell and B-cell maintenance, these observations suggested the hypothesis that signals generated by osteocytes contribute to the regulation of hematopoiesis. To test the hypothesis, Fulzele and colleagues generated mice with a conditional deletion of G S in osteocytes. G S is an obligate subunit of several G protein– coupled receptors that are expressed in osteocytes. Surprisingly, deletion of G S in osteocytes resulted in a myeloproliferative-like syndrome characterized by neutrophilia, thrombocytosis, and splenomegaly. However, unlike human myeloproliferative syndromes, the hematopoietic abnormalities did not result in increased mortality or leukemic transformation. This phenotype was secondary to an altered bone marrow microenvironment, because G S-osteocytes– deleted mice transplanted with wild-type bone marrow rapidly developed a myeloproliferative phenotype. Indeed, deletion of G S in osteocytes results in osteocyte expansion, loss of osteoblasts, and osteopenia. The authors show that increased osteocytes expression of sclerostin, a potent Wnt antagonist, is responsible for the loss of osteoblasts. However, sclerostin and osteoblast loss are not required for the myeloproliferative phenotype, because treatment with a sclerostin-neutralizing antibody, while rescuing the osteoblast defect, did not correct the leukocytosis. The authors next established a novel ex vivo co-culture system using osteocyteenriched bone explants to look for secreted factors that promote myeloid progenitor proliferation. These studies led to the discovery that osteocytes produce large amounts of granulocyte colony-stimulating factor (G-CSF), the principal cytokine regulating granulopoiesis. Although not tested in vivo, neutralizing antibodies to G-CSF inhibited the ability of osteocyte-conditioned media to stimulate myeloid progenitor growth in vitro, providing direct evidence that G-CSF, at least partially, drives the myeloproliferative phenotype in G S-osteocytes– deleted mice. Consistent with this conclusion, transgenic mice Osteocyte regulation of hematopoiesis. Osteocytes imbedded in bone communicate with cells in the bone marrow through canaliculi. Osteocytes are known to produce RANKL, which activates osteoclasts (OCs), and the Wnt antagonist sclerostin, which suppresses osteoblasts (OBs). The present study by Fulzele et al shows that osteocytes also produce G-CSF (and potentially other myelopoiesis-stimulating factors) that results in hematopoietic progenitor cell (HPC) proliferation and increased neutrophil and monocyte production.1