Mechano growth factor E peptide promotes osteoblasts proliferation and bone-defect healing

To assess the potential efficacy of mechano growth factor (MGF) for bone injury, we firstly investigated the effects of growth factors, including MGF, its E peptide (a short 24-amino acid C-terminal peptide, MGF-Ct24E), and insulin-like growth factor 1(IGF-1) on MC3T3-E1 osteoblast-like cell proliferation. MGF-Ct24E had the highest pro-proliferation activity among three growth factors, which was 1.4 times greater than that of IGF-1. Moreover, MGF-Ct24E promoted cell proliferation by inducing cell cycle arrest in the S and G2/M phase of the cell cycle, but also mainly by the activation of the MAPK-Erk1/2 pathway. In vivo, a 5-mm segmental bone defect in the radius of 27 rabbits was treated with MGF-Ct24E by two doses (28.5 and 57 μg /kg body weight) vs. non-growth factor injection for five consecutive days postoperatively. The cumulative rate of radiographically healed defects and histological scores of bone defect-healing revealed a statistical difference between high-dose treatment and non-treatment (p < 0.01), which showed the treatment promoted defect healing. This report is the first to demonstrate that MGF-Ct24E possesses positive effects on osteoblast proliferation and bone-defect healing, suggesting a new strategy in fracture healing.

Introduction

Large resections around bone tumors, complications after bone fracture, or inflammatory bone diseases often result in major bone loss or bone defect. Bone defect healing is one of the challenges of orthopaedic surgery, for which bone grafts are widely used [1415 and 17]. However, bone grafts have several drawbacks limiting their ude, including the high donor-site morbidity and a high complication rate. In search of alternative therapies, growth factors gain a significant importance. IGF-1 is one of the main growth factors in the human body and has an important role in bone injury repair, among its many functions [1516]. The igf-1 gene can be alternatively spliced to generate different IGF-1 isoforms with different functions. MGF is the initial splice-variant of IGF-1 when tissue or cells suffer from damage in some way such as mechanical/press overload, ischemia, hyperthermia, acidification, or myotoxic/ neurotoxic agents [16]. And MGF has a unique E domain (MGF-Ct24E) in the C-terminal resulting from a 48 bp insert during the splicing of exons 5 and 6, which distinguishes MGF from other IGF-1 isoforms in peptide sequence and function [79].

MGF initially was appreciated as exerting post-mitotic reparative effects in skeletal muscle [9], but more recent reports have demonstrated that MGF or MGF-Ct24E acts as a local tissue repair factor in acute injury models of muscle [37], cardiac muscle [10] and neurons [49].

Our previous study demonstrated that MGF was upregulated in MC3T3-E1 osteoblasts in response to mechanical overload [12]. Moreover, the growth of osteoblasts and bone marrow-derived MSCs (bone marrow mesenchymal stem cells) was improved by IGF-1 treatment [1819]. It is thus appealing to speculate whether the splice-variant of IGF-I, MGF or its E peptide, has positive effects on MC3T3-E1 cells action and bone fracture healing. It is well accepted that IGF-1 delivery induced bone growth mainly through the PI3K / Akt pathway [21], while some literature demonstrated that MGF-Ct24E, did not activate Akt signalling [920]. Thus, it appears attractive for the signalling of MGF-Ct24E in osteoblasts. In this study, the effects of MGF, MGF-Ct24E and IGF-1 on MC3T3-E1 cell proliferation were compared, and the signalling pathways activated by MGF-Ct24E were characterised. Then a pilot in vivo study was undertaken to confirm the role of MGF-Ct24E on the bone defect healing.

Full report below
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167400/

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