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Impact of FGF1 on human periodontal ligament fibroblast growth, osteogenic differentiation and inflammatory reaction in vitro

Einfluss von FGF1 auf Wachstum, osteogene Differenzierung und inflammatorische Stressreaktion humaner Parodontalligamentfibroblasten in vitro

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Abstract

Purpose

To investigate in vitro the impact of fibroblast growth factor 1 (FGF1) in comparison to ascorbic acid (AscA) on human periodontal ligament fibroblast (HPdLF) growth, their osteogenic differentiation, and modulation of their inflammatory reaction to mechanical stress.

Methods

The influence of different concentrations of FGF1 (12.5–200 ng/mL) on growth and proliferation of HPdLF cells was analyzed over 20 days by counting cell numbers and the percentage of Ki67-positive cells. Quantitative expression analysis of genes encoding the osteogenic markers alkaline phosphatase (ALPL), Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteopontin (OSP), as well as the fibroblast markers vimentin (VIM) and fibroblast-specific protein 1 (FSP1), was performed after 2 and 20 days of cultivation. Metabolic activity was determined by MTT assay. For comparison with AscA, 50 ng/mL FGF1 was used for stimulation for 2 and 20 days. Cell number, percentage of Ki67-positive cells, and expression of osteoblast- and fibroblast-specific genes were examined. Alkaline phosphatase activity was visualized by NBT/BCIP and calcium deposits were stained with alizarin red. Cytokine (IL‑6, IL‑8, COX2/PGE2) expression and secretion were analyzed by qPCR and ELISA in 6 h mechanically compressed HPdLF cultured for 2 days with FGF1 or ascorbic acid.

Results

Higher concentrations of FGF1 promoted cell proliferation upon short-term stimulation, whereas prolonged treatment induced the expression of osteogenic markers even with low concentrations. AscA promotes cell growth more markedly than FGF1 in short-term cultures, whereas FGF1 induced osteogenic cell fate more strongly in long-term culture. Both factors induced an increased inflammatory response of HPdLF to mechanical compression.

Conclusion

Our data suggest that FGF1 promotes an osteogenic phenotype of HPdLF and limits inflammatory response to mechanical forces compared to AscA.

Zusammenfassung

Zielsetzung

In-vitro-Evaluation des Einflusses von Fibroblastenwachstumsfaktor 1 (FGF1) im Vergleich zu Ascorbinsäure (AscA) auf das Wachstum, das osteogene Differenzierungspotenzial und die inflammatorische Stressreaktion humaner Parodontalligamentfibroblasten (HPdLF).

Methoden

Der Einfluss von verschiedenen Konzentrationen von FGF1 (12,5–200 ng/ml) auf das Wachstum und die Proliferation von HPdLF-Zellen wurde über 20 Tage anhand von Zellzahlen und dem Anteil an Ki67-positiven Zellen analysiert. Die quantitative Expressionsanalyse von Genen, welche für die osteogenen Marker alkalische Phosphatase (ALPL), „runt-related transcription factor 2“ (RUNX2), Osteocalcin (OCN) und Osteopontin (OSP) sowie für die Fibroblastenmarker Vimentin (VIM) und „fibroblast-specific protein 1“ (FSP1) kodieren, wurde nach 2 und 20 Tagen Kultivierung durchgeführt. Die metabolische Aktivität wurde mittels MTT-Assay bestimmt. Für den Vergleich mit AscA wurde 50 ng/ml FGF1 zur Stimulation für 2 und 20 Tage verwendet. Die Zellzahl, der Anteil Ki67-positiver Zellen und die Expression von osteoblasten- und fibroblastenspezifischen Genen wurden untersucht. Die Aktivität der alkalischen Phosphatase wurde mittels NBT/BCIP visualisiert und Kalziumablagerungen mit Alizarin-Rot angefärbt. Die Expression und die Sezernierung von Zytokinen (IL‑6, IL‑8, COX2/PGE2) wurden mittels qPCR und ELISA in 6 h mechanisch komprimierten HPdLF analysiert, die 2 Tage mit FGF1 oder Ascorbinsäure kultiviert wurden.

Ergebnisse

Höhere Konzentrationen von FGF1 förderten die Zellproliferation bei Kurzzeitstimulation, während bei längerer Behandlung auch mit niedrigen Konzentrationen die Expression osteogener Marker induziert wurde. AscA förderte das Zellwachstum in Kurzzeitkulturen deutlicher als FGF1, wohingegen FGF1 den osteogenen Phänotyp bei Langzeitkultivierung stärker hervorrief. Beide Faktoren induzierten eine erhöhte inflammatorische Reaktion von HPdLF auf mechanische Kompression.

Schlussfolgerung

Unsere Daten deuten darauf hin, dass FGF1 den osteogenen Phänotyp von HPdLF bei Langzeitkultivierung fördert und die immunologische Stressreaktion auf mechanische Kräfte im Vergleich zu AscA mindert.

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Acknowledgements

The authors thank the Medical Faculty of Jena, Germany, for scientific support. In addition, the authors thank Katrin von Brandenstein for her technical support. Parts of this study were awarded with the Best Presented Poster Award (Parallel Symposium) at the 92nd Scientific Annual Meeting of the German Orthodontic Society in Nuremberg, Germany 2019.

Funding

This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University (OC1‑1, OC1‑2, OC1-3) and the German Orthodontic Society (DGKFO).

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Authors and Affiliations

  1. Department of Orthodontics, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany

    Isabel Knaup DDS, Asisa Bastian & Michael Wolf

  2. Department of Orthodontics, Jena University Hospital, Jena, Germany

    Judit Symmank & Collin Jacobs

  3. Helmholtz Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University, Aachen, Germany

    Sabine Neuss

  4. Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany

    Sabine Neuss

  5. Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, Wendlingweg 2, 52074, Aachen, Germany

    Thomas Pufe

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  1. Isabel Knaup DDS
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  7. Michael Wolf
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Contributions

I. Knaup designed the study, performed experiments, data analysis and wrote the manuscript, J. Symmank designed the study, performed experiments, data analysis, figure illustration and wrote the manuscript, A. Bastian performed experiments, data analysis and critically revised the manuscript, S. Neuss, T. Pufe, C. Jacobs critically revised the manuscript, and M. Wolf designed the study and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Isabel Knaup DDS.

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Conflict of interest

I. Knaup, J. Symmank, A. Bastian, S. Neuss, T. Pufe, C. Jacobs and M. Wolf declare that they have no financial or nonfinancial competing interests.

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This article does not report on any studies with human participants or animals that were performed by any of the authors.

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The authors Isabel Knaup and Judit Symmank contributed equally to the manuscript.

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Knaup, I., Symmank, J., Bastian, A. et al. Impact of FGF1 on human periodontal ligament fibroblast growth, osteogenic differentiation and inflammatory reaction in vitro. J Orofac Orthop 83 (Suppl 1), 42–55 (2022). https://doi.org/10.1007/s00056-021-00363-6

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  • DOI: https://doi.org/10.1007/s00056-021-00363-6

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