title: Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice.
abstract: Gorham-Stout disease (GSD) is a rare bone disorder characterized by aggressive osteolysis associated with lymphatic vessel invasion within bone marrow cavities. The etiology of GSD is not known, and there is no effective therapy or animal model for the disease. Here, we investigated if lymphatic endothelial cells (LECs) affect osteoclasts (OCs) to cause a GSD osteolytic phenotype in mice. We examined the effect of a mouse LEC line on osteoclastogenesis in co-cultures. LECs significantly increased receptor activator of NF-κB ligand (RANKL)-mediated OC formation and bone resorption. LECs expressed high levels of macrophage colony-stimulating factor (M-CSF), but not RANKL, interleukin-6 (IL-6), and tumor necrosis factor (TNF). LEC-mediated OC formation and bone resorption were blocked by an M-CSF neutralizing antibody or Ki20227, an inhibitor of the M-CSF receptor, c-Fms. We injected LECs into the tibias of wild-type (WT) mice and observed massive osteolysis on X-ray and micro-CT scans. Histology showed that LEC-injected tibias had significant trabecular and cortical bone loss and increased OC numbers. M-CSF protein levels were significantly higher in serum and bone marrow plasma of mice given intra-tibial LEC injections. Immunofluorescence staining showed extensive replacement of bone and marrow by podoplanin+ LECs. Treatment of LEC-injected mice with Ki20227 significantly decreased tibial bone destruction. In addition, lymphatic vessels in a GSD bone sample were stained positively for M-CSF. Thus, LECs cause bone destruction in vivo in mice by secreting M-CSF, which promotes OC formation and activation. Blocking M-CSF signaling may represent a new therapeutic approach for treatment of patients with GSD. Furthermore, tibial injection of LECs is a useful mouse model to study GSD. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: The 1st Affiliated Hospital, Xinxiang Medical University, Xinxiang, China.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.|Institute of Stomatology, Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Xichao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dellinger
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.|Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.|Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
mesh_terms: D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D015850:Interleukin-6 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood*; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010015:Osteolysis, Essential / Q000097:blood*; D053245:RANK Ligand / Q000378:metabolism; D013977:Tibia / Q000378:metabolism / Q000473:pathology
chemical_list: D015850:Interleukin-6; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C577686:interleukin-6, mouse; D016173:Macrophage Colony-Stimulating Factor
keywords: BONE RESORPTION; GORHAM-STOUT DISEASE; LYMPHATIC ENDOTHELIAL CELLS; M-CSF; OSTEOCLASTS