title: Healing of osteoporotic bone defects by baculovirus-engineered bone marrow-derived MSCs expressing MicroRNA sponges.
abstract: 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.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Kuei-Chang
authors.initials: KC
authors.lastname: Li
authors.affiliation: Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; Department of Orthopaedic, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Yeh
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: ychu@mx.nthu.edu.tw.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Hu
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics*; D001854:Bone Marrow Cells / Q000378:metabolism*; D017102:Fracture Healing; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D010024:Osteoporosis / Q000473:pathology*; D010052:Ovariectomy; D051381:Rats; D055114:X-Ray Microtomography
chemical_list: D035683:MicroRNAs
keywords: BMP2; Bone defect; MicroRNA; Osteoporosis; miR-214; miRNA sponge