PTH1-34 improves bone healing by promoting angiogenesis and facilitating MSCs migration and differentiation in a stabilized fracture mouse model

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.

Exploring the Mechanism of Total Flavonoids of Drynariae Rhizoma to Improve Large Bone Defects by Network Pharmacology and Experimental Assessment

“…In the network, the orange points represented the candidates, the yellow points presented the therapeutic targets with weak linkage to osteogenesis and the huge green points stood for the core targets, being defined based on existing studies and data. Runt-related transcription factor 2 (RUNX-2), vascular endothelial grow factor (VEGF), fibroblast growth factor receptor 2 (FGFR2) and CD31 (platelet/endothelial cell adhesion molecule) had biological function of coupling osteogenic differentiation with angiogenesis( Kawane et al, 2018 ; Qiao et al, 2018 ; Jiang et al, 2019 ). Semaphorin 3A played an essential role in regulating the osteogenic differentiation to promote bone regeneration( Zhang et al, 2018 ).…”

Effects of Helioxanthin Derivative-Treated Human Dental Pulp Stem Cells on Fracture Healing

“…BMSCs circulate throughout the body after intravenous administration, the administered BMSCs are mostly retained in the lungs, and the homing rate to fractures is 1-2%. In this study, we demonstrated that DPSCs fluorescently stained with PKH26 and transplanted were localized in the fracture site [31,32]. Moreover, transplanted DPSCs stained with PKH26 showed mature osteoblasts by SP7 expression.…”

Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis

“…However, combination treatment in systemic applying of MSCs for bone engineering is a less explored area of research. Most of researches focus on protein molecule or ultrasound which could promote the effects on the angiogenesis efficiency of MSCs, such as erythropoietin (EPO) [ 38 ], LIPUS [ 49 ], and PTH1-34 [ 55 ]; some combination treatments could have a direct effect on osteogenesis, such as IGF-I [ 58 ] and BMP2 [ 45 ]; some protein molecules could increase the homing of transplanted MSCs to bone, such as LLP2A-Ale [ 43 , 52 ] and PTH1-34 [ 55 ]. Besides, hypoxic was detected to be an effective way to improve the survival rate, recruitment, and osteogenesis of MSCs in transplantation, and its effects were mainly achieved through the SDF-1/CXCR4 axis [ 36 ].…”