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



Women 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.
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Xian
X
Liu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Chongyun
C
Bao
Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Dental School, Baltimore, MD 21201, USA; Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Mechanical Engineering Department, University of Maryland, Baltimore County, MD 21250, USA.
Hockin H K
HHK
Xu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Jian
J
Pan
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Jing
J
Hu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Dental School, Baltimore, MD 21201, USA. Electronic address: pwang@umaryland.edu.
Ping
P
Wang
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: luoen521125@sina.com.
En
E
Luo
D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D017886:Durapatite / Q000737:chemistry*; D005260:Female; D006801:Humans; D008334:Mandible / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010024:Osteoporosis / Q000473:pathology* / Q000628:therapy*; D053244:Osteoprotegerin / Q000235:genetics* / Q000378:metabolism; D010052:Ovariectomy; D016062:Porosity; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D054457:Tissue Scaffolds / Q000737:chemistry*; D014162:Transfection; D055114:X-Ray Microtomography
D053244:Osteoprotegerin; D017886:Durapatite; D000071681:Tartrate-Resistant Acid Phosphatase
BMSCs; Bone regeneration; Gene therapy; Osteoprotegerin; Ovariectomy