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

Lu Zhou,Kyu Yun Jang,Sun Jung Yoon,Jung Ryul Kim,Byung-Hyun Park,Sajeev Wagle,Kwang Bok Lee,Young Jae Moon,Damian Christopher Genetos

doi:10.1371/journal.pone.0110593

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.

Highlights

Ischemic necrosis of the femoral head (INFH) is a relentless process in which ischemia and subsequent defective bone repair lead to collapse of the femoral head [1,2]
Vandermeer et al reported that the local administration of Bone morphogenetic protein-2 (BMP-2) after INFH in a piglet model resulted in increased bone resorption and a similar degree of head deformity compared with animals in the untreated group [13]
We demonstrate that local administration of COMP-Ang1 and BMP-2 enhances bone formation and prevents femoral head deformity through potentiation of BMP-2 signaling pathways and induction of angiogenesis in a surgically induced INFH rat model

Summary

Introduction

Ischemic necrosis of the femoral head (INFH) is a relentless process in which ischemia and subsequent defective bone repair lead to collapse of the femoral head [1,2]. INFH can lead to permanent deformity of the femoral head, severely compromised hip joint longevity, and production of premature end-stage osteoarthritis as early as the third decade of life [3]. Because total hip replacement is unsuitable for the young, active patient population, the goal of early treatment for INFH is to prevent the development of femoral head deformities [4]. BMP-2 has been shown to stimulate osteoblast recruitment, new bone formation, and angiogenesis under fracture-healing and spinal fusion conditions [7,8,9]. Vandermeer et al reported that the local administration of BMP-2 after INFH in a piglet model resulted in increased bone resorption and a similar degree of head deformity compared with animals in the untreated group [13]

Methods

Results

Conclusion