Effects Of Parathyroid Hormone (1-34) On Vascularized Bone Regeneration And Implant Osseointegration In Aged Rats

Aging affects the quality and quantity of bone,as well as alters the local microenvironment within the bone and bone marrow tissues.It attenuates bone regeneration potential and osteogenic ability in elderly patients,which may consequently make a great challenge in short-term and long-term restoration of maxillofacial bone defect.Parathyroid hormone(PTH)(1-34)is the only available osteoanabolic drug approved by the US Food and Drug Administration(FDA).It has been in clinical use to increase low bone mass in aging and osteoporosis for more than a decade.However,it is unclear from the report whether or not PTH works in improving the microenvironment of bone marrow and promoting bone regeneration and osseointegration in aging.Purpose: 1.Investigate the direct effects of intermittent PTH(1-34)on the microenvironment of bone marrow and endothelial cell migration and blood vessel formation.2.Investigate the function and mechanism of intermittent PTH(1-34)on osteoclasts to induce osteogenesis of Bone marrow stromal cells(BMSCs)and vascularization of endothelial cells indirectly.3.Demonstrate the effects of intermittent PTH(1-34)on vascularized bone regeneration and osseointegration in aged rats.Methods: 1.We isolated BMSCs from aged rats with or without intermittent PTH(1-34)treatment to gain further insights into its direct effects on aged BMSCs osteogenic and adipogenic differentiation in vitro.Furthermore,we reported the direct effects of PTH(1-34)on migration and blood vessel formation of human umbilical vein endothelial cells(HUVECs)in vitro.2.We cultured primary osteoclasts from murine bone marrow and collected osteoclast conditioned medium to coculture with HUVECs or BMSCs to test the recruitment and angiogenic abilities of HUVECs or the migration and osteogenic differentiation effects on BMSCs in vitro.3.Daily subcutaneously injections of 30 ?g/kg PTH(1-34)were given to female rats aged 20 months beginning on the day of implantation and lasting for 5 weeks.The effects of PTH(1-34)on vascularized bone regeneration and implant osseointegration were evaluated by radiological,histological and western blot analysis.Results: 1.PTH(1-34)was shown to enhance the osteogenic potential of aged BMSCs,while their adipogenesis capacity was attenuated.In addition,PTH(1-34)could promote angiogenesis directly via endothelial cell migration and blood vessel formation in vitro.2.Intermittent PTH(1-34)increased the number of osteoclasts in the epiphysis of bone,as more osteoclasts participated in bone remodeling.And the osteoclasts help to secrete angiogenic and osteogenic growth factors to induce early vascularization and stimulate the migration or differentiation of BMSCs indirectly.3.Intermittent PTH(1-34)therapy apparently improves bone collagen content,angiogenesis,bone remodeling and new bone formation in aged rats,which consequently facilitates dental implant osseointegration.Conclusion: Intermittent PTH(1-34)regulates directly or indirectly the angiogenic and osteogenic microenvironment to result in more active bone remodeling and new bone formation,which provide therapy perspective and theory foundation for rapid vascularized bone regeneration and implant osseointegration in the aged population.