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

ABSTRACT: OBJECTIVE:PTH1-34 (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. METHODS:Mice with stabilized fracture were assigned to 4 groups: CON, PTH (PTH1-34 40 ?g/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. RESULTS:Treatment 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 ?50?m), whereas MSCs increased the large ones (diameter >50?m). 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. CONCLUSIONS:PTH1-34 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.

SUBMITTER: Jiang X

PROVIDER: S-EPMC6903750 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Jiang Xin X Xu Cuidi C Shi Hongli H Cheng Qun Q

PloS one 20191210 12

<h4>Objective</h4>PTH1-34 (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.<h4>Methods</h4>Mice with stabilized fracture were assigned to 4 groups: CO ...[more]

PMID: 31821371

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Project description:BackgroundHyperbaric oxygen therapy (HBOT) consists of intermittently administering 100% oxygen at pressures greater than one atmosphere absolute (ATA) in a pressure vessel. This technology has been used to treat a variety of diseases and has been described as helping patients who have delayed healing or established non-union of bony fractures. This is an update of a Cochrane Review first published in 2005, and previously updated in 2008.ObjectivesThe aim of this review is to assess the evidence for the benefit of hyperbaric oxygen treatment (HBOT) for the treatment of delayed bony healing and established non-union of bony fractures.Search methodsWe searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (July 2012), the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7), MEDLINE (1946 to July Week 1 2012), EMBASE (1974 to 2012 July 16), CINAHL (1937 to 17 July 2012), the Database of Randomised Controlled Trials in Hyperbaric Medicine (accessed July 2012), the WHO International Clinical Trials Registry Platform (17 July 2012) and reference lists of articles.Selection criteriaWe aimed to include all randomised controlled trials comparing the clinical effects of HBOT with no HBOT (no treatment or sham) for healing of bony fractures and fracture non-unions.Data collection and analysisTwo review authors independently screened electronic search results, and all three authors independently performed study selection. We planned independent data collection and risk of bias assessment by two authors using standardised forms.Main resultsNo trials met the inclusion criteria. In this update, we identified three ongoing randomised controlled trials. Among the eight excluded studies were three randomised trials comparing HBOT with no treatment that included patients with fractures. One of these trials had been abandoned and the other two did not report on fracture healing outcomes.Authors' conclusionsThis systematic review failed to locate any relevant clinical evidence to support or refute the effectiveness of HBOT for the management of delayed union or established non-union of bony fractures. Good quality clinical trials are needed to define the role, if any, of HBOT in the treatment of these injuries. There are three randomised controlled trials underway and we anticipate these will help provide some relevant clinical evidence to address this issue in the future.

Project description:Matrix proteoglycans such as biglycan (Bgn) dominate skeletal tissue and yet its exact role in regulating bone function is still unclear. In this paper we describe the potential role of (Bgn) in the fracture healing process. We hypothesized that Bgn could regulate fracture healing because of previous work showing that it can affect normal bone formation. To test this hypothesis, we created fractures in femurs of 6-week-old male wild type (WT or Bgn+/0) and Bgn-deficient (Bgn-KO or Bgn-/0) mice using a custom-made standardized fracture device, and analyzed the process of healing over time. The formation of a callus around the fracture site was observed at both 7 and 14 days post-fracture in WT and Bgn-deficient mice and immunohistochemistry revealed that Bgn was highly expressed in the fracture callus of WT mice, localizing within woven bone and cartilage. Micro-computed tomography (μCT) analysis of the region surrounding the fracture line showed that the Bgn-deficient mice had a smaller callus than WT mice. Histology of the same region also showed the presence of less cartilage and woven bone in the Bgn-deficient mice compared to WT mice. Picrosirius red staining of the callus visualized under polarized light showed that there was less fibrillar collagen in the Bgn-deficient mice, a finding confirmed by immunohistochemistry using antibodies to type I collagen. Interestingly, real time RT-PCR of the callus at 7 days post-fracture showed a significant decrease in relative vascular endothelial growth factor A (VEGF) gene expression by Bgn-deficient mice as compared to WT. Moreover, VEGF was shown to bind directly to Bgn through a solid-phase binding assay. The inability of Bgn to directly enhance VEGF-induced signaling suggests that Bgn has a unique role in regulating vessel formation, potentially related to VEGF storage or stabilization in the matrix. Taken together, these results suggest that Bgn has a regulatory role in the process of bone formation during fracture healing, and further, that reduced angiogenesis could be the molecular basis.

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

Publications

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

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