Journal
BIOMATERIALS
Volume 74, Issue -, Pages 155-166Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.09.046
Keywords
Osteoporosis; Bone defect; MicroRNA; miR-214; BMP2; miRNA sponge
Funding
- National Tsing Hua University [104N2050E1, 103N2758E1]
- CGMH Intramural Project [CMRPG3E0441, CMRPG3E0061, CMRPG3E0062, CMRPG3B1542]
- Ministry of Science and Technology, Taiwan [101-2628-E-007-009-MY3, 101-2923-E-007-002-MY3, MOST 103-2221-E-007-093-MY3]
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Fractures associated with osteoporosis are a worldwide health problem. To augment osteoporotic bone healing, we aimed to develop a cell/gene therapy approach in combination with miRNA manipulation. We unraveled aberrant overexpression of miR-140* and miR-214 in the bone marrow-derived MSCs isolated from ovariectomized (OVX) rats (OVX-BMSCs). To suppress the miRNA levels, we constructed hybrid baculovirus vectors expressing miRNA sponges to antagonize miR-140* or miR-214. Engineering OVX-BMSCs with the hybrid vectors persistently attenuated the cellular miR-140*/miR-214 levels, which promoted the OVX-BMSCs osteogenesis and augmented the ability of OVX-BMSCs to repress osteoclast maturation in vitro. Notably, suppressing miR-214 exerted more potent osteoinductive effects. In the osteoporotic rat models with a critical-size bone defect at the femoral metaphysis, implanting the OVX-BMSCs ectopically expressing BMP2 failed to heal the defect, which underscored the difficulty to heal osteoporotic bone defects. Nonetheless, allotransplantation of the miR-214 sponges-expressing OVX-BMSCs healed the defect and ameliorated the bone quality (density, trabecular number, trabecular thickness and trabecular space) at 4 weeks post-implantation. Co-expressing BMP2 and miR-214 sponges in OVX-BMSCs further synergistically substantiated the healing. The baculovirus-engineered OVX-BMSCs that expressed miR-214 sponge, with or without BMP2 expression, thus paved a new avenue to the treatment of osteoporotic bone defects. (C) 2015 Published by Elsevier Ltd.
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