Inhibition of Gap-Junctional Communication Induces the Trans-differentiation of Osteoblasts to an Adipocytic Phenotype in Vitro

Paul C Schiller, Gianluca D'Ippolito, Roberta Brambilla, Bernard A. Roos, Guy Howard

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Osteoblasts and adipocytes are thought to differentiate from a common stromal progenitor cell. These two phenotypically mature cell types show a high degree of plasticity, which can be observed when cells are grown under specific culture conditions. Gap junctions are abundant among osteoblastic cells in vivo and in vitro, whereas they are down-regulated during adipogenesis. Gap junctional communication (GJC) modulates the expression of genes associated with the mature osteoblastic phenotype. Inhibition of GJC utilizing 18-α-glycyrrhetinic acid (AGRA) blocks the maturation of preosteoblastic cells in vitro. Moreover, cytoplasmic lipid droplets are detectable at the end of the culture period, suggesting that GJC inhibition may favor an adipocytic phenotype. We used several human osteoblastic cell lines, as well as bone-derived primary osteoblastic cells, to show that confluent cultures of human osteoblastic cells grown under osteogenic conditions developed an adipocytic phenotype after 3 days of complete inhibition of GJC using AGRA or oleamide, two dissimilar non-toxic reversible inhibitors. Development of an adipogenic phenotype was confirmed by the accumulation of triglyceride droplets and the increase in mRNA expression of the adipocytic markers peroxisome proliferator-activated receptor γ2 and lipoprotein lipase. Glycyrrhizic acid, a noninhibitory AGRA analog, or α-bromopalmitate, a nondegradable fatty acid, had no effect. Modulation of skeletal GJC may represent a new pharmacological target by which inhibition of marrow adipogenesis can take place with the parallel enhancement of osteoblastogenesis, thus providing a novel therapeutic approach to the treatment of human age-related osteopenic diseases and postmenopausal osteoporosis.

Original languageEnglish
Pages (from-to)14133-14138
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number17
StatePublished - Apr 27 2001

Fingerprint

Osteoblasts
Communication
Phenotype
Adipogenesis
Cells
Glycyrrhetinic Acid
Glycyrrhizic Acid
Peroxisome Proliferator-Activated Receptors
Lipoprotein Lipase
Postmenopausal Osteoporosis
Cell culture
Gap Junctions
Plasticity
Stromal Cells
Bone
Adipocytes
Triglycerides
Fatty Acids
Genes
Modulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of Gap-Junctional Communication Induces the Trans-differentiation of Osteoblasts to an Adipocytic Phenotype in Vitro. / Schiller, Paul C; D'Ippolito, Gianluca; Brambilla, Roberta; Roos, Bernard A.; Howard, Guy.

In: Journal of Biological Chemistry, Vol. 276, No. 17, 27.04.2001, p. 14133-14138.

Research output: Contribution to journalArticle

@article{1a2d4c7abb714db39b27c922ef74485c,
title = "Inhibition of Gap-Junctional Communication Induces the Trans-differentiation of Osteoblasts to an Adipocytic Phenotype in Vitro",
abstract = "Osteoblasts and adipocytes are thought to differentiate from a common stromal progenitor cell. These two phenotypically mature cell types show a high degree of plasticity, which can be observed when cells are grown under specific culture conditions. Gap junctions are abundant among osteoblastic cells in vivo and in vitro, whereas they are down-regulated during adipogenesis. Gap junctional communication (GJC) modulates the expression of genes associated with the mature osteoblastic phenotype. Inhibition of GJC utilizing 18-α-glycyrrhetinic acid (AGRA) blocks the maturation of preosteoblastic cells in vitro. Moreover, cytoplasmic lipid droplets are detectable at the end of the culture period, suggesting that GJC inhibition may favor an adipocytic phenotype. We used several human osteoblastic cell lines, as well as bone-derived primary osteoblastic cells, to show that confluent cultures of human osteoblastic cells grown under osteogenic conditions developed an adipocytic phenotype after 3 days of complete inhibition of GJC using AGRA or oleamide, two dissimilar non-toxic reversible inhibitors. Development of an adipogenic phenotype was confirmed by the accumulation of triglyceride droplets and the increase in mRNA expression of the adipocytic markers peroxisome proliferator-activated receptor γ2 and lipoprotein lipase. Glycyrrhizic acid, a noninhibitory AGRA analog, or α-bromopalmitate, a nondegradable fatty acid, had no effect. Modulation of skeletal GJC may represent a new pharmacological target by which inhibition of marrow adipogenesis can take place with the parallel enhancement of osteoblastogenesis, thus providing a novel therapeutic approach to the treatment of human age-related osteopenic diseases and postmenopausal osteoporosis.",
author = "Schiller, {Paul C} and Gianluca D'Ippolito and Roberta Brambilla and Roos, {Bernard A.} and Guy Howard",
year = "2001",
month = "4",
day = "27",
language = "English",
volume = "276",
pages = "14133--14138",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "17",

}

TY - JOUR

T1 - Inhibition of Gap-Junctional Communication Induces the Trans-differentiation of Osteoblasts to an Adipocytic Phenotype in Vitro

AU - Schiller, Paul C

AU - D'Ippolito, Gianluca

AU - Brambilla, Roberta

AU - Roos, Bernard A.

AU - Howard, Guy

PY - 2001/4/27

Y1 - 2001/4/27

N2 - Osteoblasts and adipocytes are thought to differentiate from a common stromal progenitor cell. These two phenotypically mature cell types show a high degree of plasticity, which can be observed when cells are grown under specific culture conditions. Gap junctions are abundant among osteoblastic cells in vivo and in vitro, whereas they are down-regulated during adipogenesis. Gap junctional communication (GJC) modulates the expression of genes associated with the mature osteoblastic phenotype. Inhibition of GJC utilizing 18-α-glycyrrhetinic acid (AGRA) blocks the maturation of preosteoblastic cells in vitro. Moreover, cytoplasmic lipid droplets are detectable at the end of the culture period, suggesting that GJC inhibition may favor an adipocytic phenotype. We used several human osteoblastic cell lines, as well as bone-derived primary osteoblastic cells, to show that confluent cultures of human osteoblastic cells grown under osteogenic conditions developed an adipocytic phenotype after 3 days of complete inhibition of GJC using AGRA or oleamide, two dissimilar non-toxic reversible inhibitors. Development of an adipogenic phenotype was confirmed by the accumulation of triglyceride droplets and the increase in mRNA expression of the adipocytic markers peroxisome proliferator-activated receptor γ2 and lipoprotein lipase. Glycyrrhizic acid, a noninhibitory AGRA analog, or α-bromopalmitate, a nondegradable fatty acid, had no effect. Modulation of skeletal GJC may represent a new pharmacological target by which inhibition of marrow adipogenesis can take place with the parallel enhancement of osteoblastogenesis, thus providing a novel therapeutic approach to the treatment of human age-related osteopenic diseases and postmenopausal osteoporosis.

AB - Osteoblasts and adipocytes are thought to differentiate from a common stromal progenitor cell. These two phenotypically mature cell types show a high degree of plasticity, which can be observed when cells are grown under specific culture conditions. Gap junctions are abundant among osteoblastic cells in vivo and in vitro, whereas they are down-regulated during adipogenesis. Gap junctional communication (GJC) modulates the expression of genes associated with the mature osteoblastic phenotype. Inhibition of GJC utilizing 18-α-glycyrrhetinic acid (AGRA) blocks the maturation of preosteoblastic cells in vitro. Moreover, cytoplasmic lipid droplets are detectable at the end of the culture period, suggesting that GJC inhibition may favor an adipocytic phenotype. We used several human osteoblastic cell lines, as well as bone-derived primary osteoblastic cells, to show that confluent cultures of human osteoblastic cells grown under osteogenic conditions developed an adipocytic phenotype after 3 days of complete inhibition of GJC using AGRA or oleamide, two dissimilar non-toxic reversible inhibitors. Development of an adipogenic phenotype was confirmed by the accumulation of triglyceride droplets and the increase in mRNA expression of the adipocytic markers peroxisome proliferator-activated receptor γ2 and lipoprotein lipase. Glycyrrhizic acid, a noninhibitory AGRA analog, or α-bromopalmitate, a nondegradable fatty acid, had no effect. Modulation of skeletal GJC may represent a new pharmacological target by which inhibition of marrow adipogenesis can take place with the parallel enhancement of osteoblastogenesis, thus providing a novel therapeutic approach to the treatment of human age-related osteopenic diseases and postmenopausal osteoporosis.

UR - http://www.scopus.com/inward/record.url?scp=0035957918&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035957918&partnerID=8YFLogxK

M3 - Article

VL - 276

SP - 14133

EP - 14138

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 17

ER -