title: TNFα contributes to diabetes impaired angiogenesis in fracture healing.
abstract: Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lim
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kang I
authors.initials: KI
authors.lastname: Ko
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Mattos
authors.affiliation: Department of Endocrinology, Shanxi Province People's Hospital, Shanxi Province, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Implantology, School of Stomatology, Jilin University, Changchun 130021, China.
authors.forename: Citong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Feinberg
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hisham
authors.initials: H
authors.lastname: Sindi
authors.affiliation: Department of Implant Dentistry, Peking University, School and Hospital of Stomatology, Beijing, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Oral Basic and Clinical Sciences, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jazia
authors.initials: J
authors.lastname: Alblowi
authors.affiliation: Department of Oral Basic and Clinical Sciences, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Rayyan A
authors.initials: RA
authors.lastname: Kayal
authors.affiliation: Department of Orthopedic Surgery, School of Medicine, Boston University, Boston, MA 02118, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Einhorn
authors.affiliation: Department of Orthopedic Surgery, School of Medicine, Boston University, Boston, MA 02118, USA.
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dtgraves@upenn.edu.
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D005169:Factor VIII / Q000378:metabolism; D017102:Fracture Healing / Q000187:drug effects* / Q000276:immunology; D006943:Hyperglycemia / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000097:blood; D011092:Polyethylene Glycols / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D018952:Antigens, CD34; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols; D005169:Factor VIII; C577771:PEGylated soluble tumor necrosis factor receptor I
keywords: Blood vessel; Bone; Cytokine; Endothelial; Forkhead; Hyperglycemia; Inflammation; VEGF; Vascularization