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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 ?3 and ?1 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.

SUBMITTER: Zhou L

PROVIDER: S-EPMC4201557 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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COMP-angiopoietin1 potentiates the effects of bone morphogenic protein-2 on ischemic necrosis of the femoral head in rats.

Zhou Lu L Yoon Sun Jung SJ Jang Kyu Yun KY Moon Young Jae YJ Wagle Sajeev S Lee Kwang Bok KB Park Byung-Hyun BH Kim Jung Ryul JR

PloS one 20141017 10

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 (sha ...[more]

PMID: 25329960

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Project description:BackgroundIschemic necrosis of the femoral head can be induced surgically in the piglet. We used this model to assess femoral head deformation and repair in vivo by sequential magnetic resonance imaging and by correlating end-stage findings with histologic assessments.MethodsIschemic necrosis of the femoral head was induced in ten three-week-old piglets by tying a silk ligature around the base of the femoral neck (intracapsular) and cutting the ligamentum teres. We used magnetic resonance imaging with the piglets under general anesthesia to study the hips at forty-eight hours and at one, two, four, and eight weeks. Measurements on magnetic resonance images in the midcoronal plane of the involved and control sides at each time documented the femoral head height, femoral head width, superior surface cartilage height, and femoral neck-shaft angle. Histologic assessments were done at the time of killing.ResultsComplete ischemia of the femoral head was identified in all involved femora by magnetic resonance imaging at forty-eight hours. Revascularization began at the periphery of the femoral head as early as one week and was underway in all by two weeks. At eight weeks, magnetic resonance imaging and histologic analysis showed deformation of the femoral head and variable tissue deposition. Tissue responses included (1) vascularized fibroblastic ingrowth with tissue resorption and cartilage, intramembranous bone, and mixed fibro-osseous or fibro-cartilaginous tissue synthesis and (2) resumption of endochondral bone growth. At eight weeks, the mean femoral head measurements (and standard error of the mean) for the control compared with the ligated femora were 10.4 +/- 0.4 and 4.8 +/- 0.4 mm, respectively, for height; 26.7 +/- 0.8 and 31.2 +/- 0.8 mm for diameter; 1.1 +/- 0.1 and 2.3 +/- 0.1 mm for cartilage thickness; and 151 degrees +/- 2 degrees and 135 degrees +/- 2 degrees for the femoral neck-shaft angle. Repeated-measures mixed-model analysis of variance revealed highly significant effects of ligation in each parameter (p < 0.0001).ConclusionsMagnetic resonance imaging allows for the assessment of individual hips at sequential time periods to follow deformation and repair. There was a variable tissue response, and histologic assessment at the time of killing was shown to correlate with the evolving and varying magnetic resonance imaging signal intensities. Femoral head height on the ischemic side from one week onward was always less than the initial control value and continually decreased with time, indicating collapse as well as slowed growth. Increased femoral head width occurred relatively late (four to eight weeks), indicating cartilage model overgrowth concentrated at the periphery.

Dataset Information

COMP-angiopoietin1 potentiates the effects of bone morphogenic protein-2 on ischemic necrosis of the femoral head in rats.

Publications

COMP-angiopoietin1 potentiates the effects of bone morphogenic protein-2 on ischemic necrosis of the femoral head in rats.

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