Abstract
The effect of dual delivery of bone morphogenetic protein-2 (BMP-2) and matrix metalloproteinase 10 (MMP10) on bone regeneration was investigated in a murine model of calvarial critical-size defect, hypothesizing that it would result in an enhanced bone formation. Critical-size calvarial defects (4 mm diameter) were created in mice and PLGA microspheres preloaded with either BMP-2, MMP10 or a microsphere combination of both were transplanted into defect sites at different doses. Empty microspheres were used as the negative control. Encapsulation efficiency was assessed and in vivo release kinetics of BMP-2 and MMP10 were examined over 14 days. Histological analyses were used to analyze bone formation after four and eight weeks. Combination with MMP10 (30 ng) significantly enhanced BMP-2 (600 ng)-mediated osteogenesis, as confirmed by the increase in percentage of bone fill (p < .05) at four weeks. Moreover, it also increased mineral apposition rate (p < .05), measured by double labeling with tetracycline and calceine. MMP10 accelerates bone repair by enhancing BMP-2-promoted bone healing and improving the mineralization rate. In conclusion combination of MMP10 and BMP-2 may become a promising strategy for repair and regeneration of bone defects.
Highlights
A profibrinolytic function has been reported for active matrix metalloproteinase 10 (MMP10), by enhancing tissue plasminogen activator-dependent fibrinolysis (Orbe et al, 2011)
In the present study, using a controlled release system, we investigated whether MMP10 can enhance bone morphogenetic protein-2 (BMP-2)-promoted bone repair in vivo, in a murine model of critical-size bone defect
After the initial burst effect observed with M-125I-Matrix metalloproteinases (MMPs), higher than that of M-125I-bone morphogenetic proteins (BMPs), the release rate during the period from the first to the 10th day was slower, 4.4% of MMP10/day against 6.1% of BMP-2/day
Summary
Growth factors (GFs) of TGFb family, including bone morphogenetic proteins (BMPs), play important roles in skeletal development (Chen et al, 2012). BMP-2, one of the most important cytokines regulating osteoblasts differentiation, plays relevant roles in a variety of cellular functions ranging from embryogenesis, cell growth, and differentiation to bone development and the repair of bone fractures (Rosen, 2009; Dimitriou et al, 2011). MMPs have pivotal functions in physiology and pathophysiology, playing important roles in cancer and in normal development, wound healing and tissue remodeling after damage. MMP10 has been shown to be involved in tissue repair processes using different experimental models of damage, such as hind limb ischemia (Gomez-Rodrıguez et al, 2015), skeletal muscle (Bobadilla et al, 2014) and liver injury (Garcıa-Irigoyen et al, 2014)
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