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Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signalling Enhances Osteogenesis in UMR-106 Cell Line

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Abstract

Presence of the pituitary adenylate cyclase-activating polypeptide (PACAP) signalling has been proved in various peripheral tissues. PACAP can activate protein kinase A (PKA) signalling via binding to pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1), vasoactive intestinal polypeptide receptor (VPAC) 1 or VPAC2 receptor. Since little is known about the role of this regulatory mechanism in bone formation, we aimed to investigate the effect of PACAP on osteogenesis of UMR-106 cells. PACAP 1-38 as an agonist and PACAP 6-38 as an antagonist of PAC1 were added to the culture medium. Surprisingly, both substances enhanced protein expressions of collagen type I, osterix and alkaline phosphatase, along with higher cell proliferation rate and an augmented mineralisation. Although expression of PKA was elevated, no alterations were detected in the expression, phosphorylation and nuclear presence of CREB, but increased nuclear appearance of Runx2, the key transcription factor of osteoblast differentiation, was shown. Both PACAPs increased the expressions of bone morphogenetic proteins (BMPs) 2, 4, 6, 7 and Smad1 proteins, as well as that of Sonic hedgehog, PATCH1 and Gli1. Data of our experiments indicate that activation of PACAP pathway enhances bone formation of UMR-106 cells and PKA, BMP and Hedgehog signalling pathways became activated. We also found that PACAP 6-38 did not act as an antagonist of PACAP signalling in UMR-106 cells.

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Abbreviations

ALP:

Alkaline phosphatase

BMP:

Bone morphogenetic protein

cAMP:

Cyclic adenosine monophosphate

CNS:

Central nervous system

CREB:

cAMP response element-binding protein

DMEM:

Dulbecco’s modified Eagle’s medium

dNTP:

Deoxynucleotide triphosphate

ECM:

Extracellular matrix

EDTA:

Ethylenediaminetetraacetic acid

FBS:

Foetal bovine serum

FGF:

Fibroblast growth factor

HH:

Hedgehog

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

hMSC:

Human mesenchymal stem cell

IHH:

Indian hedgehog

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PAC1:

Pituitary adenylate cyclase-activating polypeptide type I receptor

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PBS:

Phosphate-buffered saline

PBST:

Phosphate-buffered saline supplemented with 1 % Tween 20

PLC:

Phospholipase C

PKA:

Protein kinase A

PKC:

Protein kinase C

PTHrP:

Parathyroid hormone-related peptide

RT-PCR:

Reverse transcription followed by polymerase chain reaction

Runx2:

Runt-related transcription factor 2

SHH:

Sonic hedgehog

TBE:

Tris-boric acid-EDTA

TGFβ:

Transforming growth factor-β

VEGF:

Vascular endothelial growth factor

VIP:

Vasoactive intestinal polypeptide

VPAC:

Vasoactive intestinal polypeptide receptor

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Acknowledgments

The authors are grateful for Mrs. Krisztina Bíró and Mrs. Ella Kovács for excellent technical assistance during the study. This work was supported by grants from Akira Arimura Foundation Research Grant, the Hungarian Science Research Fund (OTKA CNK80709 and OTKA K 104984), Bolyai Scholarship and the Hungarian Ministry of Education (TÁMOP 4.2.1.B-10/2/KONV-2010-002, PTE-MTA “Lendület” Program) and from the New Széchenyi Plan (TÁMOP-4.2.2.A-11/1/KONV-2012-0053, TÁMOP-4.2.2.A-11/1/KONV-2012-0024). The project is co-financed by the European Union and the European Social Fund. This research and T.J. was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 “National Excellence Program”. C.M. is supported by a Mecenatura grant (DEOEC Mec-9/2011) from the Medical and Health Science Center, University of Debrecen, Hungary.

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Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032, Debrecen, Hungary

    Tamás Juhász, Csaba Matta, Éva Katona, Csilla Somogyi, Roland Takács, Tibor Hajdú, Solveig Lind Helgadottir & Róza Zákány

  2. Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032, Debrecen, Hungary

    János Fodor & László Csernoch

  3. Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary

    Gábor Tóth

  4. Cell Biology and Signalling Research Group of the Hungarian Academy of Sciences, Department of Medical Chemistry, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032, Debrecen, Hungary

    Éva Bakó

  5. Department of Anatomy, PTE-MTA “Lendület” PACAP Research Team, University of Pécs, Medical School, Szigeti út 12, H-7624, Pécs, Hungary

    Dóra Reglődi & Andrea Tamás

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  1. Tamás Juhász
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  2. Csaba Matta
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  14. Róza Zákány
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Correspondence to Róza Zákány.

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Juhász, T., Matta, C., Katona, É. et al. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signalling Enhances Osteogenesis in UMR-106 Cell Line. J Mol Neurosci 54, 555–573 (2014). https://doi.org/10.1007/s12031-014-0389-1

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  • DOI: https://doi.org/10.1007/s12031-014-0389-1

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