Nicotinic acetylcholine receptors modulate osteoclastogenesis

Peter Mandl, Silvia Hayer, Thomas Karonitsch, Petra Scholze, David Gyori, Despoina Sykoutri, Stephan Blüml, A. Mócsai, G. Poór, Sigismund Huck, Josef S. Smolen, Kurt Redlich

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis. Methods: The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis. Oscillations in the intracellular calcium concentration were detected by measuring the Fura-2 fluorescence intensity. Results: We could demonstrate the presence of several nAChR subunits in bone marrow-derived macrophages stimulated with RANKL and M-CSF, and showed that they are capable of producing acetylcholine. nAChR ligands reduced the number of osteoclasts as well as the number of tartrate-resistant acidic phosphatase-positive mononuclear cells in a dose-dependent manner. In vitro RANKL-mediated osteoclastogenesis was reduced in mice lacking α7 homomeric nAChR or β2-containing heteromeric nAChRs, while bone histomorphometry revealed increased bone volume as well as impaired osteoclastogenesis in male mice lacking the α7 nAChR. nAChR ligands inhibited RANKL-induced calcium oscillation, a well-established phenomenon of osteoclastogenesis. This inhibitory effect on Ca2+ oscillation subsequently led to the inhibition of RANKL-induced NFATc1 and c-fos expression after long-term treatment with nicotine. Conclusions: We have shown that the activity of nAChRs conveys a marked effect on osteoclastogenesis in mice. Agonists of these receptors inhibited calcium oscillations in osteoclasts and blocked the RANKL-induced activation of c-fos and NFATc1. RANKL-mediated in-vitro osteoclastogenesis was reduced in α7 knockout mice, which was paralleled by increased tibial bone volume in male mice in vivo.

Original languageEnglish
Article number63
JournalArthritis Research and Therapy
Volume18
Issue number1
DOIs
Publication statusPublished - Mar 12 2016

Fingerprint

RANK Ligand
Nicotinic Receptors
Osteogenesis
Bone and Bones
Macrophage Colony-Stimulating Factor
Calcium Signaling
Osteoclasts
Macrophages
Ligands
Fura-2
Nicotine
Phosphoric Monoester Hydrolases
Knockout Mice
Acetylcholine
Real-Time Polymerase Chain Reaction
Flow Cytometry
Homeostasis
Fluorescence
Western Blotting
Tomography

Keywords

  • Acetylcholine receptor
  • Nicotine
  • Osteoclastogenesis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy

Cite this

Mandl, P., Hayer, S., Karonitsch, T., Scholze, P., Gyori, D., Sykoutri, D., ... Redlich, K. (2016). Nicotinic acetylcholine receptors modulate osteoclastogenesis. Arthritis Research and Therapy, 18(1), [63]. https://doi.org/10.1186/s13075-016-0961-x

Nicotinic acetylcholine receptors modulate osteoclastogenesis. / Mandl, Peter; Hayer, Silvia; Karonitsch, Thomas; Scholze, Petra; Gyori, David; Sykoutri, Despoina; Blüml, Stephan; Mócsai, A.; Poór, G.; Huck, Sigismund; Smolen, Josef S.; Redlich, Kurt.

In: Arthritis Research and Therapy, Vol. 18, No. 1, 63, 12.03.2016.

Research output: Contribution to journalArticle

Mandl, P, Hayer, S, Karonitsch, T, Scholze, P, Gyori, D, Sykoutri, D, Blüml, S, Mócsai, A, Poór, G, Huck, S, Smolen, JS & Redlich, K 2016, 'Nicotinic acetylcholine receptors modulate osteoclastogenesis', Arthritis Research and Therapy, vol. 18, no. 1, 63. https://doi.org/10.1186/s13075-016-0961-x
Mandl P, Hayer S, Karonitsch T, Scholze P, Gyori D, Sykoutri D et al. Nicotinic acetylcholine receptors modulate osteoclastogenesis. Arthritis Research and Therapy. 2016 Mar 12;18(1). 63. https://doi.org/10.1186/s13075-016-0961-x
Mandl, Peter ; Hayer, Silvia ; Karonitsch, Thomas ; Scholze, Petra ; Gyori, David ; Sykoutri, Despoina ; Blüml, Stephan ; Mócsai, A. ; Poór, G. ; Huck, Sigismund ; Smolen, Josef S. ; Redlich, Kurt. / Nicotinic acetylcholine receptors modulate osteoclastogenesis. In: Arthritis Research and Therapy. 2016 ; Vol. 18, No. 1.
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