title: The Angiopoietin-1 Variant COMP-Ang1 Enhances BMP2-Induced Bone Regeneration with Recruiting Pericytes in Critical Sized Calvarial Defects.
abstract: Craniofacial bone defects are observed in a variety of clinical situations, and their reconstructions require coordinated coupling between angiogenesis and osteogenesis. In this study, we explored the effects of cartilage oligomeric matrix protein-angiopoietin 1 (COMP-Ang1), a synthetic and soluble variant of angiopoietin 1, on bone morphogenetic protein 2 (BMP2)-induced cranial bone regeneration, and recruitment and osteogenic differentiation of perivascular pericytes. A critical-size calvarial defect was created in the C57BL/6 mouse and COMP-Ang1 and/or BMP2 proteins were delivered into the defects with absorbable collagen sponges. After 3 weeks, bone regeneration was evaluated using micro-computed tomography and histologic examination. Pericyte recruitment into the defects was examined using immunofluorescence staining with anti-NG2 and anti-CD31 antibodies. In vitro recruitment and osteoblastic differentiation of pericyte cells were assessed with Boyden chamber assay, staining of calcified nodules, RT-PCR and Western blot analyses. Combined administration of COMP-Ang1 and BMP2 synergistically enhanced bone repair along with the increased population of CD31 (an endothelial cell marker) and NG2 (a specific marker of pericyte) positive cells. In vitro cultures of pericytes consistently showed that pericyte infiltration into the membrane pore of Boyden chamber was more enhanced by the combination treatment. In addition, the combination further increased the osteoblast-specific gene expression, including bone sialoprotein (BSP), osteocalcin (OCN) and osterix (OSX), phosphorylation of Smad/1/5/8, and mineralized nodule formation. COMP-Ang1 can enhance BMP2-induced cranial bone regeneration with increased pericyte recruitment. Combined delivery of the proteins might be a therapeutic strategy to repair cranial bone damage.
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hyuck
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Sung-Woong
authors.initials: SW
authors.lastname: Hur
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Orthopedic Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Keun-Bae
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Koh
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D001861:Bone Regeneration / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D058574:Integrin-Binding Sialoprotein / Q000096:biosynthesis; D051379:Mice; D015675:Osteocalcin / Q000096:biosynthesis; D010012:Osteogenesis / Q000235:genetics*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D012886:Skull / Q000254:growth & development* / Q000293:injuries / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C515576:COMP-Ang1 fusion protein; D058574:Integrin-Binding Sialoprotein; D011993:Recombinant Fusion Proteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin