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Abstract
Communication between osteoblasts and endothelial cells (ECs) is essential for bone turnover, but the molecular mechanisms of such communication are not well defined. Here we identify Cxcl9 as an angiostatic factor secreted by osteoblasts in the bone marrow microenvironment. We show that Cxcl9 produced by osteoblasts interacts with vascular endothelial growth factor and prevents its binding to ECs and osteoblasts, thus abrogating angiogenesis and osteogenesis both in mouse bone and in vitro. The mechanistic target of rapamycin complex 1 activates Cxcl9 expression by transcriptional upregulation of STAT1 and increases binding of STAT1 to the Cxcl9 promoter in osteoblasts. These findings reveal the essential role of osteoblast-produced Cxcl9 in angiogenesis and osteogenesis in bone, and Cxcl9 can be targeted to elevate bone angiogenesis and prevent bone loss-related diseases.
Bone development and vascularization are coupled events that share many molecular mechanisms. Here the authors identify osteoblast-secreted Cxcl9 as an inhibitory regulator of angiogenesis and osteogenesis, and show that mTORC1 signaling and STAT1 are critical upstream mediators of the cytokine expression.
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Details
1 Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Department of Orthopedics, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
2 State Key Laboratory of Organ Failure Research, School of Basic Medical Science, Southern Medical University, Department of Cell Biology, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
3 University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000)
4 Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Department of Orthopedics, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471); State Key Laboratory of Organ Failure Research, School of Basic Medical Science, Southern Medical University, Department of Cell Biology, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)