Nicotine acts on growth plate chondrocytes to delay skeletal growth through the α7 neuronal nicotinic acetylcholine receptor

Atsuo Kawakita, Kazuki Satou, Hatsune Makino, Hiroyasu Ikegami, Shinichiro Takayama, Yoshiaki Toyama, Akihiro Umezawa

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Cigarette smoking adversely affects endochondral ossification during the course of skeletal growth. Among a plethora of cigarette chemicals, nicotine is one of the primary candidate compounds responsible for the cause of smoking-induced delayed skeletal growth. However, the possible mechanism of delayed skeletal growth caused by nicotine remains unclarified. In the last decade, localization of neuronal nicotinic acetylcholine receptor (nAChR), a specific receptor of nicotine, has been widely detected in non-excitable cells. Therefore, we hypothesized that nicotine affect growth plate chondrocytes directly and specifically through nAChR to delay skeletal growth. Methodology/Principal Findings: We investigated the effect of nicotine on human growth plate chondrocytes, a major component of endochondral ossification. The chondrocytes were derived from extra human fingers. Nicotine inhibited matrix synthesis and hypertrophic differentiation in human growth plate chondrocytes in suspension culture in a concentration-dependent manner. Both human and murine growth plate chondrocytes expressed alpha7 nAChR, which constitutes functional homopentameric receptors. Methyllycaconitine (MLA), a specific antagonist of alpha7 nAChR, reversed the inhibition of matrix synthesis and functional calcium signal by nicotine in human growth plate chondrocytes in vitro. To study the effect of nicotine on growth plate in vivo, ovulation-controlled pregnant alpha7 nAChR +/- mice were given drinking water with or without nicotine during pregnancy, and skeletal growth of their fetuses was observed. Maternal nicotine exposure resulted in delayed skeletal growth of alpha7 nAChR +/+ fetuses but not in alpha7 nAChR -/- fetuses, implying that skeletal growth retardation by nicotine is specifically mediated via fetal alpha7 nAChR. Conclusions/Significance: These results suggest that nicotine, from cigarette smoking, acts directly on growth plate chondrocytes to decrease matrix synthesis, suppress hypertrophic differentiation via alpha7 nAChR, leading to delayed skeletal growth.

Original languageEnglish
Article numbere3945
JournalPLoS One
Volume3
Issue number12
DOIs
Publication statusPublished - 2008 Dec 16

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growth plate
Growth Plate
cholinergic receptors
nicotine
chondrocytes
Nicotinic Receptors
Chondrocytes
Nicotine
alpha7 Nicotinic Acetylcholine Receptor
Growth
human growth
fetus
Fetus
smoking (habit)
Tobacco Products
Smoking
bone formation
Osteogenesis
synthesis
Maternal Exposure

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nicotine acts on growth plate chondrocytes to delay skeletal growth through the α7 neuronal nicotinic acetylcholine receptor. / Kawakita, Atsuo; Satou, Kazuki; Makino, Hatsune; Ikegami, Hiroyasu; Takayama, Shinichiro; Toyama, Yoshiaki; Umezawa, Akihiro.

In: PLoS One, Vol. 3, No. 12, e3945, 16.12.2008.

Research output: Contribution to journalArticle

Kawakita, Atsuo ; Satou, Kazuki ; Makino, Hatsune ; Ikegami, Hiroyasu ; Takayama, Shinichiro ; Toyama, Yoshiaki ; Umezawa, Akihiro. / Nicotine acts on growth plate chondrocytes to delay skeletal growth through the α7 neuronal nicotinic acetylcholine receptor. In: PLoS One. 2008 ; Vol. 3, No. 12.
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