Abstract
ObjectivePTH1-34 (parathyroid hormone 1–34) is the only clinical drug to promote osteogenesis. MSCs (mesenchymal stem cells) have multidirectional differentiation potential and are closely related to fracture healing. This study was to explore the effects of PTH1-34 on proliferation and differentiation of endothelial cells and MSCs in vitro, and on angiogenesis, and MSCs migration during fracture healing in vivo.MethodsMice with stabilized fracture were assigned to 4 groups: CON, PTH (PTH1-34 40 μg/kg/day), MSC (transplanted with 105 MSCs), PTH+MSCs. Mice were sacrificed 14 days after fracture, and callus tissues were harvested for microCT scan and immunohistochemistry analysis. The effects of PTH1-34 on angiogenesis, and MSCs differentiation and migration were assessed by wound healing, tube formation and immunofluorescence staining.ResultsTreatment with either PTH1-34, or MSCs promoted bone healing and vascular formation in fracture callus. The callus bone mass, bone volume, and bone mineral density were all greater in PTH and/or MSC groups than they were in CON (p<0.05). PTH1-34 increased small vessels formation (diameter ≤50μm), whereas MSCs increased the large ones (diameter >50μm). Expression of CD31 within calluses and trabecular bones were significantly higher in PTH1-34 treated group than that of not (p<0.05). Expression of CD31, VEGFR, VEGFR2, and vWF was upregulated, and wound healing and tube formation were increased in MSCs treated with PTH1-34 compared to that of control.ConclusionsPTH1-34 improved the proliferation and differentiation of endothelial cells and MSCs, enhancing migration of MSCs to bone callus to promote angiogenesis and osteogenesis, and facilitating fracture healing.
Highlights
Delayed healing and nonunion of fractures are enormous burdens on patients and health care systems
The callus bone mass, bone volume, and bone mineral density were all greater in PTH and/or Mesenchymal stem cells (MSCs) groups than they were in CON (p
The animals were randomly divided into four groups (n = 12 per group): (1) CON, mice were administrated with BSA; (2) PTH1-34, mice were administrated with PTH1-34 (Genekey Biotech, China)40ug/kg/d;(3)BM-MSCs transplatation, mice were administrated with BM-MSCs isolated from C57BL/6J mice 105 tail vein injection; (4) PTH+BM-MSCs transplatation, mice were administrated with PTH 40ug/kg/d subcutaneously and BM-MSCs 105 tail vein injection
Summary
Delayed healing and nonunion of fractures (collectively referred to as DNFs) are enormous burdens on patients and health care systems. In the context of delayed/nonunion, fragile fractures in osteoporotic populations are associated with significant patient morbidity, loss of productivity, decreased quality of life, and extensive health-care utilization[2,3]. But have the potential to transdifferentiate into certain cell lineages: endothelial cells[7,8,9] Recent studies both in vitro and in vivo utilizing animal models clearly identified bone marrow-derived MSCs as important contributors to the formation of new blood vessels in adults[10] in a process known as angiogenesis. Recent advances in identifying and cloning the many factors associated with angiogenic activity have renewed the interest in the possibility that the repair of difficult fractures can be enhanced. Some studies have confirmed an increase in blood flow and vascularity during the repair of fractured bone[11,12]
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