Thrombopoietic Agents: Novel Osteoinductive Agents for Bone Healing
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PROVIDER: PRJNA627964 | ENA |
REPOSITORIES: ENA
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Project description:Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically BMPs , has gained wide appreciable attention. However, multiple side effects, including increased incidence of cancer, has renewed interest in investigating other alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte growth factor, thrombopoietin (TPO) and/or second generation TPO agents in mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical sized defect or CSD and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances angiogenesis, an important aspect of successful bone repair. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (e.g. thrombocytopenia).
2020-07-24 | GSE149329 | GEO
Project description:Osteoinductive biodegradable intramedullary implant accelerates bone healing and mitigates complications in a rat bone transport model
| PRJNA824864 | ENA
Project description:Although cellular and molecular mechanisms during the course of bone healing have been thoroughly investigated, the regulation of gene expression by microRNA during bone regeneration is still poorly understood. We hypothesized that nonunion formation is associated with different microRNA expression patterns and that target proteins of these microRNAs are differently expressed in callus tissue of nonunions compared to physiologically healing bones. In a well-established femoral osteotomy model in CD-1 mice osteotomies were induced which result either in healing or in nonunion formation. MicroRNA and target protein expression was evaluated by microarray, quantitative real-time polymerase chain reaction (qrt-PCR) and Western blot. Microarray analyses demonstrated 44 microRNAs to be relevant for nonunion formation compared to physiological bone healing. In nonunions qrt-PCR could validate a higher expression of microRNA-140-3p and microRNA-140-5p. This was associated with a reduced expression of Dnpep and stromal cell-derived factor (SDF)-1α, which are both known to be target proteins of microRNA-140 and also to be involved in the process of bone healing. These data suggest that an increased expression of microRNA-140-3p and mi-croRNA-140-5p markedly contributes to the development of nonunions, most probably by affecting bone morphogenetic protein (BMP)-2 function during the early stage of healing due to a reduced SDF-1α expression.
2019-06-27 | GSE133243 | GEO
Project description:Clinical evidence has established that concomitant traumatic brain injury accelerates bone healing, but the underlying mechanism is unclear. This study showed that after TBI, injured neurons, mainly those in the hippocampus, released osteogenic microRNA (miRNA)-enriched exosomes, which targeted osteoprogenitors in bone to stimulate bone formation. Importantly, increased fibronectin expression on exosomal surface contributed to targeting of osteoprogenitors in bone by TBI exosomes, thereby implying that modification of the exosome surface fibronectin could be used in bone-targeted drug delivery. Together, our findings have established a novel role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings.
2021-07-13 | PXD022126 | Pride
Project description:Bone transport distraction osteogenesis (DO) is one of the most successful surgery-driven endogenous tissue regeneration approaches for the treatment of large bone defects. However, prolonged consolidation, docking site nonunion, and pin tract infection remain challenging complications. Here, we engineered an osteoinductive, biodegradable intramedullary (IM) implant for sustained release of bone morphogenetic protein-2 (BMP-2) as an adjunctive therapy of bone transport to address the clinical challenges. A hybrid tissue engineering construct (HyTEC) technique was developed to enable sustained release of BMP-2 in a broad range. 100% bony fusion was achieved in the IM implants incorporating with 2 μg and 6 μg BMP-2 as early as 34 days after bone transport surgeries in the management of 8-mm femoral defect. Load bearing was restored 55 days after surgeries when the fixator was removed. Eluting BMP-2 from the IM implants accelerates bone formation and angiogenesis at early phase, and increase mineralization at late phase, especially at the docking sites, leading to early bony bridging. Moreover, no pin tract infection but seamless integration could be found in the 2 μg and 6 μg BMP-2 treated groups. Surgical control and IM implant showed high proportion of non-union and pin tract infections. 2 μg BMP-2 delivered by collagen sponge or 0.5 μg BMP-2-laden IM implant did not induce bone regeneration effectively, resulting in some non-unions and infections. A presence of bacteria of fecal origin in the infection sites was identified. In conclusion, this osteoinductive IM implant holds great promise in revolutionizing bone transport DO technique in the management of bone defect by accelerating bone regeneration and mitigating complications.
2023-06-09 | GSE200518 | GEO
Project description:Bone fracture healing shows approximately 10-15% non-unions, although theoretically it has the potential of scarless regeneration. With regards to our aging society, a better understanding of the healing process is needed to allow for more sophisticated treatment options. Particular the early phase, which is a high complex and dynamic process in regards to nutrient and engery requirements. Here we investigate the proteomic (and metabolic) characteristics of the local microenvironment from successful (in young female Sprague-Dawley rats) and biologically compromised (in aged female rats with a minimum litter of three)bone reneration at day 3, 7 and 14 after osteotomy.
2023-05-10 | PXD020085 | Pride
Project description:The fracture hematoma that forms between the broken fragments of bone serves as a natural fibrin scaffold. However, there is no data regarding the differences between the micro-architectural and biological properties of hematomas formed in normally healing, delayed healing, and non-healing bone defects. Mimicking these three conditions in the rat femur, we demonstrate clear differences in fibrin clot morphology, which directly affect the gene expression pattern. Specifically, RNA-sequencing reveals that the expression of essential osteogenic genes in normally healing defects are significantly up-regulated, whereas in delayed and non-healing defects they are down-regulated. Surprisingly, there were no substantial differences between delayed and non-healing defects. Most importantly, this study demonstrates that the healing outcome has already been determined at the earliest stage of bone healing. These findings could be used to develop biomaterial scaffolds mimicking the micro-architectural properties of normally healing fracture hematoma as a treatment strategy for bone defects. The hypothesis of this study was that the micro-architectural properties of the initially formed hematoma has a significant effect on the regulation of the biological process at the fracture site, which ultimately determines the outcome of bone healing. Three different healing models were investigated - normally healing, delayed healing, and non-healing defects. The results demonstrated that the intrinsic micro-architectural properties of hematomas between those groups varied distinctly in terms of fiber diameter, porosity, and density of the formed fibrin network. Those differences influenced biological responses, as evidenced by a higher expression of osteogenic genes in normally healing compared to delayed and non-healing defects, and the failed activation of BMP-2 in non-healing defects. More importantly, our results demonstrate healing outcomes are already determined at the initial (hematoma) stage of bone healing.
2023-11-01 | GSE161315 | GEO
Project description:Bone is a unique organ able to regenerate after severe traumatic injuries. However, regeneration is governed by the interplay between systems located in the site of injury. The immune system initiates the inflammatory response in the early phase of healing. Therefore, the global role of T-cells and B-cells in the bone regeneration and the resulting bone quality is the focus of this study. A standard unilateral closed fracture was created in the femora to study the overlapping phases of bone healing. Besides wild type (WT) a model of recombination activating gene 1 knockout (RAG1-/-) mice that lacking mature T and B-cells were investigated. In addition, at D7 the individual role of T-cells and B-cells were investigated through the (TCRβδ) and JHT-/- knockouts respectively. Radiological, biomechanical, histological and imaging were utilized along with differential expression analysis. RAG1-/- mice showed higher biomechanical stiffness in intact bone when compared to the WT mice. Higher mineralization at early stage was seen in the RAG1-/- and bone devoid of T-cells (TCRβδ-/-) including. However, healing in bone devoid of B-cells (JHT-/-) was not apparently deviant of that of WT. Interestingly, second harmonic photon microscopy revealed an disorganized collagen fibers in the RAG1-/- contemporary with the expression analysis showing dysregulation in the expression of ColI subunits. Gene network analysis reflected the expected down regulation of T cell related genes in the RAG1-/- but not the B-cell related genes. This can hint to backup mechanism compensating the lack of mature B-cells. Furthermore, differentially expressed genes in RAG1-/- mice showed an impact on angiogenesis, cytokines & growth factors and bone remodeling, and BMP signaling array throughout the healing process. This asserts the focus on the adaptive immune system in two directions: 1) suggested role of T-cells in governing bone quality. 2) indicated importance of B-cells for bone regeneration through backup mechanisms.
2020-05-04 | GSE99128 | GEO
Project description:Genome-wide comparative gene expression analysis of callus tissue of osteoporotic mice (Col1a1-Krm2 and Lrp5-/-) and wild-type were performed to identify candidate genes that might be responsible for the impaired fracture healing observed in Col1a1-Krm2 and Lrp5-/- mice. To investigate bone healing in osteoporosis, we performed fracture healing studies in wild-type mice (C57BL/6 genetic background) and the low bone mass strains Col1a1-Krm2 and Lrp5-/- (Schulze et al., 2010; Kato et al., 2002). Osteotomy was set in femora of female mice and stabilized by a semi-rigid fixator to allow fast bone healing (RM-CM-6ntgen et al., 2010). 21 days post surgery we analyzed the fracture calli by biochemical/histological methods, as well as micro-computed tomography, and observed impaired fracture healing in Col1a1-Krm2 and Lrp5-/- mice in comparison to wild-type. To identify genes that may be responsible for the impaired healing in osteoporotic mice, we performed microarray analysis of three independent callus samples of each genotype. The callus tissue was taken 10 days after surgery, because extensive bone formation took place at this point.
2013-10-25 | E-GEOD-51686 | biostudies-arrayexpress
Project description:The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature (“Core” OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis. Keywords: cancer, transcription-profile, bone, metastasis, stroma
2014-12-09 | GSE22813 | GEO