Osteoprotegerin gene-modified BMSCs with hydroxyapatite scaffold for treating critical-sized mandibular defects in ovariectomized osteoporotic rats

Abstract

Women with postmenopausal osteoporosis are at a high risk for fracture as their bone resorption rate exceeds bone formation rate, resulting in decreased bone mineral density and microarchitectural deterioration. Osteoprotegerin (OPG), a known therapeutic agent capable of inhibiting osteoclastogenesis, has been used in treatment of chronic bone resorptive diseases. On the other hand, bone mesenchymal stem cells (BMSCs) play an important role in bone formation. To inhibit excessive bone resorption and increase bone formation, we developed a novel therapeutic strategy by genetically modifying BMSCs for OPG delivery. The OPG gene-modified BMSCs were seeded on hydroxyapatite (HA) scaffolds to promote bone regeneration in critical-sized mandibular bone defects in ovariectomy (OVX) induced osteoporotic rats. Rat BMSCs were infected with human OPG adenoviruses (OPG-BMSCs). The gene-modified cells expressed higher OPG gene level than the control Ad-BMSCs (p<0.05) and maintained high expression of OPG protein for more than 2weeks. Our in vitro bone resorption experiment demonstrated that OPG-BMSCs were capable to suppress osteoclast differentiation and subsequently inhibit osteoclast-mediated bone resorption. The micro-CT and histological results showed that HA-OPG-BMSC constructs boosted bone formation and reduced osteoclastogenesis in OVX rat mandibular bone defects. In conclusion, the novel OPG-BMSC-HA constructs were demonstrated to be able to orchestrate bone-forming BMSCs and bone-resorbing osteoclasts, with the potential for osteoporotic-related bone defect reconstruction applications. Statement of SignificanceWomen with postmenopausal osteoporosis are at a high risk for fracture as their bone resorption rate exceeds bone formation rate. Osteoprotegerin (OPG), a known therapeutic agent capable of inhibiting osteoclast cells, has been used in treatment of chronic bone resorptive diseases. To inhibit excessive bone resorption and increase bone formation, we developed a novel therapeutic strategy by genetically modifying bone marrow stem cells (BMSCs) for OPG delivery and seeding the cells on a hydroxyapatite (HA) scaffold for in vivo bone defect repair. The novel OPG-BMSC-HA constructs were able to orchestrate bone-forming BMSCs and bone-resorbing osteoclasts, demonstrating good potential for osteoporosis-related bone defect reconstruction treatments.