title: COMP-angiopoietin1 potentiates the effects of bone morphogenic protein-2 on ischemic necrosis of the femoral head in rats.
abstract: Angiogenesis is considered essential for proper bone regeneration. The purpose of this investigation was to determine if a combined therapy of bone morphogenetic protein-2 (BMP-2) and cartilage oligomeric matrix protein angiopoietin-1 (COMP-Ang1) can potentiate the therapeutic effect of BMP-2 in a rat model of ischemic necrosis of the femoral head (INFH). INFH was surgically induced in the femoral head of rats, and the animals were divided into the following groups: 1) a sham-operated group (sham group), 2) a bovine serum albumin-injected group (BSA group), 3) a BMP-2-injected group (BMP-2 group), and 4) a COMP-Ang1 and BMP-2-injected group (COMP-Ang1 + BMP-2 group) (n = 20/group). Radiologic, histologic, and histomorphometric assessments were performed to assess femoral head morphology, vascular density, and bone resorption activity. Western blots and immunohistochemical staining were performed to evaluate production of BMP-related signaling proteins in C3H10T1/2 cells and tissues. Real-time RT-PCR was performed to investigate expression of the target integrin gene, and the effect of integrin on C3H10T1/2 cells was determined using a cell adhesion assay. Radiographs obtained six weeks after injection revealed better preservation of the architecture of the femoral head in the COMP-Ang1 + BMP-2 group compared with the BSA and BMP-2 groups. Histological findings indicated increased trabecular bone and vascularity and decreased osteoclast bone resorption activity in the COMP-Ang1 + BMP-2 group compared with those in the BSA and BMP-2 groups. The combination of COMP-Ang1 and BMP-2 increased phosphorylation of Smad1/3/5, p38, and Akt. Increased integrin α3 and β1 mRNA expression in the COMP-Ang1 + BMP-2 group promoted cell adhesion. These results suggest that COMP-Ang1 preserved the necrotic femoral head through the potentiation of BMP-2 signaling pathways and angiogenesis. Combination treatment with COMP-Ang1 and BMP-2 may be a clinically useful therapeutic application in INFH.
authors.affiliation: Departments of Orthopedic Surgery, Chonbuk National University Medical School, Research Institute for Endocrine Sciences and Research Institute of Clinical Medicine, Jeonju, Republic of Korea; Department of Sports Medicine, Taishan Medical University, Shandong, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Departments of Orthopedic Surgery, Chonbuk National University Medical School, Research Institute for Endocrine Sciences and Research Institute of Clinical Medicine, Jeonju, Republic of Korea.
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Yoon
authors.affiliation: Departments of Pathology, Chonbuk National University Medical School, Research Institute for Endocrine Sciences and Research Institute of Clinical Medicine, Jeonju, Republic of Korea.
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Departments of Biochemistry, Chonbuk National University Medical School, Research Institute for Endocrine Sciences, Jeonju, Republic of Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Moon
authors.affiliation: Departments of Orthopedic Surgery, Chonbuk National University Medical School, Research Institute for Endocrine Sciences and Research Institute of Clinical Medicine, Jeonju, Republic of Korea.
authors.forename: Sajeev
authors.initials: S
authors.lastname: Wagle
authors.affiliation: Departments of Orthopedic Surgery, Chonbuk National University Medical School, Research Institute for Endocrine Sciences and Research Institute of Clinical Medicine, Jeonju, Republic of Korea.
authors.forename: Kwang Bok
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Departments of Biochemistry, Chonbuk National University Medical School, Research Institute for Endocrine Sciences, Jeonju, Republic of Korea.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: Departments of Orthopedic Surgery, Chonbuk National University Medical School, Research Institute for Endocrine Sciences and Research Institute of Clinical Medicine, Jeonju, Republic of Korea.
authors.forename: Jung Ryul
authors.initials: JR
authors.lastname: Kim
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000235:genetics; D001861:Bone Regeneration / Q000187:drug effects; D002417:Cattle; D018929:Cell Culture Techniques; D003412:Cricetulus; D005271:Femur Head Necrosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D011859:Radiography; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000235:genetics
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C515576:COMP-Ang1 fusion protein; D016023:Integrins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins