Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice.
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ABSTRACT:
SUBMITTER: Xiao L
PROVIDER: S-EPMC2631953 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Repair of bone defects remains a significant clinical problem. Bone morphogenetic protein 2 (BMP2) is US Food and Drug Administration-approved for fracture healing but is expensive and has associated morbidity. Studies have shown that targeted overexpression of the 18-kDa low-molecular-weight fibroblast growth factor 2 isoform (LMW) by the osteoblastic lineage of transgenic mice increased bone mass. This study tested the hypotheses that overexpression of LMW would directly enhance healing of a critical size calvarial bone defect in mice and that this overexpression would have a synergistic effect with low-dose administration of BMP2 on critical size calvarial bone defect healing. Bilateral calvarial defects were created in LMW transgenic male mice and control/vector transgenic (Vector) male mice and scaffold with or without BMP2 was placed into the defects. New bone formation was assessed by VIVA-computed tomography of live animals over a 27-week period. Radiographic and computed tomography analysis revealed that at all time points, healing of the defect was enhanced in LMW mice compared with that in Vector mice. Although the very low concentration of BMP2 did not heal the defect in Vector mice, it resulted in complete healing of the defect in LMW mice. Histomorphometric and gene analysis revealed that targeted overexpression of LMW in osteoblast precursors resulted in enhanced calvarial defect healing due to increased osteoblast activity and increased canonical Wnt signaling.
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Project description:Virulence of the nosocomial pathogen Staphylococcus epidermidis is crucially linked to formation of adherent biofilms on artificial surfaces. Biofilm assembly is significantly fostered by production of a bacteria derived extracellular matrix. However, the matrix composition, spatial organization, and relevance of specific molecular interactions for integration of bacterial cells into the multilayered biofilm community are not fully understood. Here we report on the function of novel 18 kDa Small basic protein (Sbp) that was isolated from S. epidermidis biofilm matrix preparations by an affinity chromatographic approach. Sbp accumulates within the biofilm matrix, being preferentially deposited at the biofilm-substratum interface. Analysis of Sbp-negative S. epidermidis mutants demonstrated the importance of Sbp for sustained colonization of abiotic surfaces, but also epithelial cells. In addition, Sbp promotes assembly of S. epidermidis cell aggregates and establishment of multilayered biofilms by influencing polysaccharide intercellular-adhesin (PIA) and accumulation associated protein (Aap) mediated intercellular aggregation. While inactivation of Sbp indirectly resulted in reduced PIA-synthesis and biofilm formation, Sbp serves as an essential ligand during Aap domain-B mediated biofilm accumulation. Our data support the conclusion that Sbp serves as an S. epidermidis biofilm scaffold protein that significantly contributes to key steps of surface colonization. Sbp-negative S. epidermidis mutants showed no attenuated virulence in a mouse catheter infection model. Nevertheless, the high prevalence of sbp in commensal and invasive S. epidermidis populations suggests that Sbp plays a significant role as a co-factor during both multi-factorial commensal colonization and infection of artificial surfaces.
| S-EPMC4370877 | biostudies-literature
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Project description:The expression of the interleukin (IL-6) gene can be regulated by various activating or inhibitory stimuli. This modulation involves several regulatory binding sites on the IL-6 promoter, and appears to be in general cell-specific. We have previously described that the nuclear 24 kDa isoform of fibroblast growth factor-2 (FGF-2) is able to increase IL-6 gene expression in NIH-3T3 cells. The transduction pathway involved was shown to be distinct from the extracellular mode of action of the smallest 18 kDa FGF-2 isoform. In the present study, we show that 24 kDa FGF-2-encoding vectors transfected into HeLa cells inhibit various co-transfected constructs incorporating the promoter element of the IL-6 gene and either the luciferase or the chloramphenicol acetyltransferase units. This down-regulation occurs dose-dependently with the 24 kDa FGF-2, is IL-6-promoter-specific, and does not involve an autocrine loop of the growth factor, since exogenously added FGF-2 fails to modulate the IL-6 promoter activity. Furthermore, 24 kDa FGF-2 inhibits the activity of both the co-transfected deletion mutants IL-6(-224) and IL-6(-158), and the point-mutated IL-6 promoter constructs in which the activating protein-1, nuclear factor (NF)-IL-6 and NF-kappaB elements are disrupted. We identify a responsive region to 24 kDa FGF-2 between positions -158 and -109 on the IL-6 promoter, which notably contains a retinoblastoma control element.
| S-EPMC1220238 | biostudies-other
Project description:Posttraumatic osteoarthritis is a disabling condition impacting the mostly young and active population. In the present study, we investigated the impact of intra-articular sprifermin, a recombinant truncated fibroblast growth factor 18, on the outcome of microfracture treatment, a widely used surgical technique to enhance cartilage healing at the site of injury. For this study, we created a cartilage defect and performed microfracture treatment in fetlock joints of 18 horses, treated joints with one of three doses of sprifermin (10, 30, or 100 μg) or with saline, hyaluronan, and evaluated animals functional and structural outcomes over 24 weeks. For primary outcome measures, we performed histological evaluations and gene expression analysis of aggrecan, collagen types I and II, and cartilage oligomeric matrix protein in three regions of interest. As secondary outcome measures, we examined animals' lameness, performed arthroscopic, radiographic, and computed tomography (CT) scan imaging and gross morphology assessment. We detected the highest treatment benefit following 100 μg sprifermin treatment. The overall histological assessment showed an improvement in the kissing region, and the expression of constitutive genes showed a concentration-dependent enhancement, especially in the peri-lesion area. We detected a significant improvement in lameness scores, arthroscopic evaluations, radiography, and CT scans following sprifermin treatment when results from three dose-treatment groups were combined. Our results demonstrated, for the first time, an enhancement on microfracture outcomes following sprifermin treatment suggesting a cartilage regenerative role and a potential benefit of sprifermin treatment in early cartilage injuries.
| S-EPMC8560655 | biostudies-literature
Project description:Pivotal in many ways for human health, the control of adult bone mass is governed by complex, incompletely understood crosstalk namely between mesenchymal stem cells, osteoblasts and osteoclasts. The SOX4, SOX11 and SOX12 (SOXC) transcription factors were previously shown to control many developmental processes, including skeletogenesis, and SOX4 was linked to osteoporosis, but how SOXC control adult bone mass remains unknown. Using SOXC loss- and gain-of-function mouse models, we show here that SOXC redundantly promote prepubertal cortical bone mass strengthening whereas only SOX4 mitigates adult trabecular bone mass accrual in early adulthood and subsequent maintenance. SOX4 favors bone resorption over formation by lowering osteoblastogenesis and increasing osteoclastogenesis. Single-cell transcriptomics reveals its prevalent expression in Lepr+ mesenchymal cells and ability to upregulate genes for prominent anti-osteoblastogenic and pro-osteoclastogenic factors, including interferon signaling-related chemokines, contributing to these adult stem cells' secretome. SOXC, with SOX4 predominantly, are thus key regulators of adult bone mass.
| S-EPMC10997656 | biostudies-literature
Project description:BackgroundSkeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.MethodsMuscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.ResultsWe show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% (P < 0.05) compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles (P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05). Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals (P < 0.05).ConclusionsFGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
| S-EPMC6596457 | biostudies-literature
Project description:Coculture of mesenchymal stem cells with chondrocytes increases production of cartilaginous matrix. Chondrocytes isolated from late stage osteoarthritic patients usually lost their phenotype of producing cartilaginous matrix. Fibroblast growth factor 18 is believed to redifferentiate OA chondrocyte into functionally active chondrocytes. The aim of this study is to investigate the supportive effects of MSCs on OA chondrocytes and test if FGF18 could enhance the responsiveness of OA chondrocytes to the support of MSCs in a coculture system. Both pellet and transwell co-cultures were used. GAG quantification, hydroxyproline assay, and qPCR were performed. An ectopic models of cartilage formation was also applied. Our data indicated that, in pellets coculture of MSCs and OA chondrocytes, matrix production was increased in the presence of FGF18, comparing to the monoculture of chondrocytes. Results from transwell coculture study showed that expression of matrix producing genes in OA chondrocytes increased when cocultured with MSCs with FGF18 in culture medium, while hypertrophic genes were not changed by coculture. Finally, coimplantation of MSCs with OA chondrocytes produces more matrix than chondrocytes only. In conclusion, FGF18 can restore the responsiveness of OA chondrocytes to the trophic effects of MSCs. Coimplantation of MSCs and OA chondrocytes treated with FGF18 may be a good alternative cell source for regenerating cartilage tissue that is degraded during OA pathological changes.
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Project description:Objectives/hypothesisThe majority of congenital airway anomalies arise from deficits in the respiratory tract cartilage, emphasizing the importance of this cartilage to the form and function of the upper airway. The primary objective of this study was to characterize molecular mechanisms that regulate rate and direction of chondrocyte growth in the larynx and trachea. Our hypothesis for this study was that fibroblast growth factor 18 (FGF18) provides proliferative and directional cues to the developing laryngeal and tracheal cartilage in the mouse by up-regulating the cartilage-specifying gene, Sox9.Study designMolecular genetic and histological analyses of gene expression and cartilage growth in a mouse model.MethodsControlled mating of wild-type FVB/N (Friend Virus B-type/NIH mouse) mice and FGF18 overexpressing mice were carried out, and embryos ranging from embryonic (E) day 10.5 to E18.5 were obtained. The respiratory tract, including the larynx, trachea, and lung, was removed through meticulous dissection, and subjected to whole-mount in situ hybridization with RNA probes, or was sectioned and subjected to immunohistochemistry. Respiratory tracts from FVB/N mice were grown in culture in the presence of exogenous FGF18 or known inhibitors of the FGF pathway, and then subjected to quantitative reverse transcriptase polymerase chain reaction to measure the expression of cartilage-specific genes.ResultsThe upper respiratory tract begins as a simple out-pouching from the ventral foregut endoderm at E10.5. The chondrocytes that form the cartilaginous structures of the upper respiratory tract are located at the junction of the respiratory tract out-pouching and the ventral foregut endoderm. This population of chondrocytes then undergoes directional proliferation to eventually assume the mature three-dimensional configuration of the upper respiratory tract cartilaginous framework. Immunohistochemical localization of extracellular signal-regulated kinases, a known modulator of FGF signaling, demonstrated the presence of this enzyme at the periphery of growing cartilage. Explants of larynx-trachea-lung grown in culture with exogenous FGF18 demonstrated hyperplastic growth and directed growth towards the FGF18 source. Finally, both FGF18 overexpressing tracheas and tracheas cultured with exogenous FGF18 demonstrated increased expression of the cartilage-specifying gene, Sox9.ConclusionsFGF18 provided both directional and proliferative cues to chondrocytes in the developing upper respiratory tract. FGF18 exerted this effect on developing chondrocytes by up-regulating Sox9 expression. Laryngoscope, 2009.
| S-EPMC2693282 | biostudies-literature
Project description:Previous studies using transgenic Pax3cre mice have revealed roles for fibroblast growth factor receptors (Fgfrs) and Fgfr substrate 2α (Frs2α) signaling in early metanephric mesenchyme patterning and in ureteric morphogenesis. The role of Fgfr/Frs2α signaling in nephron progenitors is unknown. Thus, we generated mouse models using BAC transgenic Six2EGFPcre (Six2cre) mediated deletion of Fgfrs and/or Frs2α in nephron progenitors. Six2cre mediated deletion of Fgfr1 or Fgfr2 alone led to no obvious kidney defects. Six2creFgfr1(flox/flox)Fgfr2(flox/flox) (Fgfr1/2(NP-/-)) mice generate a discernable kidney; however, they develop nephron progenitor depletion starting at embryonic day 12.5 (E12.5) and later demonstrate severe cystic dysplasia. To determine the role of Frs2α signaling downstream of Fgfr2 in Fgfr1/2(NP-/-) mice, we generated Six2cre(,)Fgfr1(flox/flox)Fgfr2(LR/LR) (Fgfr1(NP-/-)Fgfr2(LR/LR)) mice that have point mutations in the Frs2α binding site of Fgfr2. Like Fgfr1/2(NP-/-) mice, Fgfr1(NP-/-)Fgfr2(LR/LR) develop nephron progenitor depletion, but it does not start until E14.5 and older mice have less severe cystic dysplasia than Fgfr1/2(NP-/-) To determine the role of Frs2α alone in nephron progenitors, we generated Six2creFrs2'A(flox/flox) (Frs2a(NP-/-)) mice. Frs2a(NP-/-)mice also develop nephron progenitor depletion and renal cysts, although these occurred later and were less severe than in the other Six2cre mutant mice. The nephron progenitor loss in all Six2cre mutant lines was associated with decreased Cited1 expression and increased apoptosis versus controls. FAC-sorted nephron progenitors in Six2cre Frs2'A(flox/flox) mice demonstrated evidence of increased Notch activity versus controls, which likely drives the progenitor defects. Thus, Fgfr1 and Fgfr2 have synergistic roles in maintaining nephron progenitors; furthermore, Fgfr signaling in nephron progenitors appears to be mediated predominantly by Frs2α.
| S-EPMC4361332 | biostudies-literature