The effects of G-CSF and naproxen sodium on the serum TGF-β1 level and fracture healing in rat tibias

Kaygusuz, Muberra; Turan, Çiǧdem; Aydın, Nasuhi Engin; Temel, İsmail; Fırat, Serpil; Bulut, Taner; Kuku, İrfan

doi:10.1016/j.lfs.2006.08.023

Cited by 16 publications

(12 citation statements)

References 48 publications

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“…31 The rat as animal model for fracture studies. In general, the rat is predominantly used to study the effects of pharmaceuticals, [32][33][34][35][36][37][38][39][40] signalling proteins, and growth factors 38,41-44 on fracture healing with and without primary injury. Mechanical influences like ultrasound, 45 torsion stiffness 46 as well as compression and distraction 47 are examined as well but are not the predominant use for this fracture model.…”

Section: Animal Modelsmentioning

confidence: 99%

Replacement, refinement, and reduction: Necessity of standardization and computational models for long bone fracture repair in animals

Reifenrath

Angrisani

Lalk

et al. 2013

J Biomedical Materials Res

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In the field of fracture healing it is essential to know the impacts of new materials. Fracture healing of long bones is studied in various animal models and extrapolated for use in humans, although there are differences between the micro- and macrostructure of human versus animal bone. Unfortunately, recommended standardized models for fracture repair studies do not exist. Many different study designs with various animal models are used. Concerning the general principles of replacement, refinement and reduction in animal experiments (three "Rs"), a standardization would be desirable to facilitate better comparisons between different studies. In addition, standardized methods allow better prediction of bone healing properties and implant requirements with computational models. In this review, the principles of bone fracture healing and differences between osteotomy and artificial fracture models as well as influences of fixation devices are summarized. Fundamental considerations regarding animal model choice are discussed, as it is very important to know the limitations of the chosen model. In addition, a compendium of common animal models is assembled with special focus on rats, rabbits, and sheep as most common fracture models. Fracture healing simulation is a basic tool in reducing the number of experimental animals, so its progress is also presented here. In particular, simulation of different animal models is presented. In conclusion, a standardized fracture model is of utmost importance for the best adaption of simulation to experimental setups and comparison between different studies. One of the basic goals should be to reach a consensus for standardized fracture models.

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Section: Animal Modelsmentioning

confidence: 99%

Replacement, refinement, and reduction: Necessity of standardization and computational models for long bone fracture repair in animals

Reifenrath

Angrisani

Lalk

et al. 2013

J Biomedical Materials Res

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“…[40,41] There also is evidence that G-CSF treatment is associated with increased circulating TGF-β1 levels. [42] Together, these observations suggest the hypothesis that canonical TGF-β family signaling in bone marrow MSCs, by downregulating CXCL12 expression, may contribute to G-CSF induced HSC mobilization. To test this hypothesis, we first asked whether TGF-β1 regulates CXCL12 in primary murine bone marrow MSCs.…”

Section: Loss Of Smad4 In Mesenchymal Stromal Cells Does Not Affect Hmentioning

confidence: 85%

Canonical Signaling By TGF Family Members in Mesenchymal Stromal Cells Is Dispensable for Hematopoietic Niche Maintenance Under Basal and Stress Conditions

Krambs

Ezzi

Yao

et al. 2019

Blood

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The bone marrow contains a complex population of stromal and hematopoietic cells that together generate a unique microenvironment, or niche, to support hematopoiesis. Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche and include CXCL12-abundant reticular (CAR) cells, adipocytes, osteolineage cells, and arteriolar pericytes, all of which have been implicated in hematopoietic stem/progenitor cell (HSPC) maintenance. There also is evidence that adaptive changes in bone marrow stromal cells contributes to recovery from myelosuppresive therapy and the development of certain hematopoietic malignancies. However, the signals that contribute to the development, maintenance, and stress response of bone marrow mesenchymal stromal cells are poorly understood. Here, we test the hypothesis that cytokines of the transforming growth factor superfamily, which include bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and activins/inhibins, provide signals to mesenchymal stromal cells that contribute to basal and stress hematopoiesis responses. To test this hypothesis, we abrogated canonical TGF family signaling in mesenchymal stem/progenitor cells by deleting Smad4 using a doxycycline-repressible Osterix-Cre transgene (Osx-Cre), which targets all mesenchymal stromal cells in the bone marrow. We first performed lineage-tracing studies using Osx-Cre Smad4fl/fl Ai9 mice to show that activation of Osx-Cre at birth (by removal of doxycycline) results in the efficient targeting of bone marrow mesenchymal stromal cells. Moreover, we show that Smad4 mRNA expression is essentially undetectable in sorted mesenchymal stromal cells sorted from the bone marrow of these mice. Basal hematopoiesis and bone marrow stromal cells were analyzed in 6-8 week old Osx-Cre Smad4fl/fl mice. No alterations in the number or spatial organization of CAR cells, osteoblasts, or adipocytes was observed, and expression of key niche factors, including Scf, Cxcl12, and Spp1 was normal. Basal hematopoiesis, including the number of phenotypic HSCs in bone marrow and spleen, also was normal. Recent studies have shown that inhibition of activin signaling by treating with an activin receptor 2 alpha (ACVR2a) ligand trap stimulates erythropoiesis. Although ACVR2a signaling in erythroid progenitors contributes to this effect, two groups showed that inhibition of ACVR2a signaling in bone marrow stromal cells also stimulates erythropoiesis. Thus, we next characterized basal and stress erythropoiesis in Osx-Cre Smad4fl/fl mice. The frequency of phenotypic erythroid progenitors in bone marrow and spleen was similar to control mice. The stress erythropoiesis response was assessed after induction of acute hemolytic anemia by phenylhydrazine treatment. Both the magnitude of anemia and kinetics of erythroid recovery were similar to control mice. Myelosuppressive therapy induces marked alterations in the bone marrow microenvironment that includes an expansion of osteolineage cells and adipocytes, which have been linked to hematopoietic recovery. Thus, we next characterized stress hematopoiesis in Osx-Cre Smad4fl/fl mice in response to 5-fluorouracil (5-FU) treatment. Compared to control mice, the magnitude and duration of neutropenia following 5-FU were similar. Moreover, mouse survival after repeated weekly doses of 5-FU was comparable to control mice. HSPC mobilization by G-CSF is due, in large part, by downregulation of CXCL12 expression in bone marrow mesenchymal stromal cells. A prior study suggested that SMAD signaling negatively regulates CXCL12 expression in stromal cells. Consistent with this finding, we show that treatment of cultured bone marrow derived MSCs with TGF-b1 for 48 hours results in a significant (3.3-fold, P<0.0001) decrease in CXCL12 mRNA expression. Thus, in the final experiments, we characterized G-CSF induced HSPC mobilization in Osx-Cre, Smad4fl/fl or Osx-Cre, Tgfbr2fl/fl mice. HSPC mobilization, as quantified by CFU-C and Kit+ Sca+ lineage- (KSL) cell number in blood or spleen after 5 days of G-CSF treatment was comparable to control mice. Collectively, these data suggest the TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions. Disclosures No relevant conflicts of interest to declare.

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“…An earlier study reported that fracture healing in adult male rats could be accelerated by increased expression of TGF-β1 in both plasma and at the fracture site, when due to traumatic brain injury [ 29 ]. Another study revealed that the administration of naproxen sodium into bone fracture model rats decreased their TGF-β1 serum levels and resulted in a slow fracture healing for these rats, while the use of granulocyte colony stimulating factor (G-CSF) increased the TGF-β1 serum levels and led to a better fracture healing [ 30 ]. In addition, TGF-β1 released from TGF-β1-loaded microgranules promoted bone regeneration in rabbit calvarial defects after 4 weeks [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of obesity on the healing of bone fracture in mice

Gao

Zhou

et al. 2018

J Orthop Surg Res

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BackgroundObesity affects bone health to varying degrees, depending on the skeletal site (weight-bearing or non-weight-bearing) and compartment (cortical or trabecular), and is a risk factor for orthopedic disorders, including bone fractures. However, the effect and mechanisms of obesity on healing of bone fracture is little understood.MethodsThe healing bone fractures of the tibia in genetically obese mice was evaluated relative to normal mice at weekly intervals for 28 days using X-ray scans, hematoxylin and eosin (H&E) stain, and alcian blue (AB) stain. Plasma concentrations of relevant proteins were also compared via enzyme-linked immunosorbent assay (ELISA). These included calcitonin gene-related peptide (CGRP), fibroblast growth factor (FGF), transforming growth factor beta 1 (TGF-β1), and tumor necrosis factor-α (TNF-α).ResultsBone fracture healing was delayed in the obese mice compared with the control group of normal mice, based on X-ray, H&E stain, and AB stain analysis. This was accompanied with significantly low plasma CGRP, FGF, and TGF-β1 (ELISA). However, TNF-α was significantly higher in obese mice compared with the control.ConclusionBone fracture healing was significantly slower in the obese mice, relative to that of normal mice. The lower levels of CGRP, FGF, and TGF-β, and higher level of TNF-α, observed in obese mice may contribute to this observed delay in fracture healing.

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The effects of G-CSF and naproxen sodium on the serum TGF-β1 level and fracture healing in rat tibias

Cited by 16 publications

References 48 publications

Replacement, refinement, and reduction: Necessity of standardization and computational models for long bone fracture repair in animals

Replacement, refinement, and reduction: Necessity of standardization and computational models for long bone fracture repair in animals

Canonical Signaling By TGF Family Members in Mesenchymal Stromal Cells Is Dispensable for Hematopoietic Niche Maintenance Under Basal and Stress Conditions

Effects of obesity on the healing of bone fracture in mice

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