The effects of direct inhibition of geranylgeranyl pyrophosphate synthase on osteoblast differentiation

Megan M. Weivoda, Raymond Hohl

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. These effects have been attributed to the depletion of geranylgeranyl pyrophosphate (GGPP). In this study, we tested whether specific inhibition of GGPP synthase (GGPPS) with digeranyl bisphosphonate (DGBP) would similarly lead to increased osteoblast differentiation. DGBP concentration dependently decreased intracellular GGPP levels in MC3T3-E1 pre-osteoblasts and primary rat calvarial osteoblasts, leading to impaired Rap1a geranylgeranylation. In contrast to our hypothesis, 1 μM DGBP inhibited matrix mineralization in the MC3T3-E1 pre-osteoblasts. Consistent with this, DGBP inhibited the expression of alkaline phosphatase and osteocalcin in primary osteoblasts. By inhibiting GGPPS, DGBP caused an accumulation of the GGPPS substrate farnesyl pyrophosphate (FPP). This effect was observed throughout the time course of MC3T3-E1 pre-osteoblast differentiation. Interestingly, DGBP treatment led to activation of the glucocorticoid receptor in MC3T3-E1 pre-osteoblast cells, consistent with recent findings that FPP activates nuclear hormone receptors. These findings demonstrate that direct inhibition of GGPPS, and the resulting specific depletion of GGPP, does not stimulate osteoblast differentiation. This suggests that in addition to depletion of GGPP, statin-stimulated osteoblast differentiation may depend on the depletion of upstream isoprenoids, including FPP.

Original languageEnglish (US)
Pages (from-to)1506-1513
Number of pages8
JournalJournal of cellular biochemistry
Volume112
Issue number6
DOIs
StatePublished - Jun 1 2011

Fingerprint

Geranylgeranyl-Diphosphate Geranylgeranyltransferase
Osteoblasts
Farnesyltranstransferase
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Prenylation
Osteocalcin
Terpenes
Glucocorticoid Receptors
Cytoplasmic and Nuclear Receptors
Osteogenesis

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{0e0dd9093696421081abc3462afcd3b9,
title = "The effects of direct inhibition of geranylgeranyl pyrophosphate synthase on osteoblast differentiation",
abstract = "Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. These effects have been attributed to the depletion of geranylgeranyl pyrophosphate (GGPP). In this study, we tested whether specific inhibition of GGPP synthase (GGPPS) with digeranyl bisphosphonate (DGBP) would similarly lead to increased osteoblast differentiation. DGBP concentration dependently decreased intracellular GGPP levels in MC3T3-E1 pre-osteoblasts and primary rat calvarial osteoblasts, leading to impaired Rap1a geranylgeranylation. In contrast to our hypothesis, 1 μM DGBP inhibited matrix mineralization in the MC3T3-E1 pre-osteoblasts. Consistent with this, DGBP inhibited the expression of alkaline phosphatase and osteocalcin in primary osteoblasts. By inhibiting GGPPS, DGBP caused an accumulation of the GGPPS substrate farnesyl pyrophosphate (FPP). This effect was observed throughout the time course of MC3T3-E1 pre-osteoblast differentiation. Interestingly, DGBP treatment led to activation of the glucocorticoid receptor in MC3T3-E1 pre-osteoblast cells, consistent with recent findings that FPP activates nuclear hormone receptors. These findings demonstrate that direct inhibition of GGPPS, and the resulting specific depletion of GGPP, does not stimulate osteoblast differentiation. This suggests that in addition to depletion of GGPP, statin-stimulated osteoblast differentiation may depend on the depletion of upstream isoprenoids, including FPP.",
author = "Weivoda, {Megan M.} and Raymond Hohl",
year = "2011",
month = "6",
day = "1",
doi = "10.1002/jcb.23087",
language = "English (US)",
volume = "112",
pages = "1506--1513",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
number = "6",

}

The effects of direct inhibition of geranylgeranyl pyrophosphate synthase on osteoblast differentiation. / Weivoda, Megan M.; Hohl, Raymond.

In: Journal of cellular biochemistry, Vol. 112, No. 6, 01.06.2011, p. 1506-1513.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The effects of direct inhibition of geranylgeranyl pyrophosphate synthase on osteoblast differentiation

AU - Weivoda, Megan M.

AU - Hohl, Raymond

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. These effects have been attributed to the depletion of geranylgeranyl pyrophosphate (GGPP). In this study, we tested whether specific inhibition of GGPP synthase (GGPPS) with digeranyl bisphosphonate (DGBP) would similarly lead to increased osteoblast differentiation. DGBP concentration dependently decreased intracellular GGPP levels in MC3T3-E1 pre-osteoblasts and primary rat calvarial osteoblasts, leading to impaired Rap1a geranylgeranylation. In contrast to our hypothesis, 1 μM DGBP inhibited matrix mineralization in the MC3T3-E1 pre-osteoblasts. Consistent with this, DGBP inhibited the expression of alkaline phosphatase and osteocalcin in primary osteoblasts. By inhibiting GGPPS, DGBP caused an accumulation of the GGPPS substrate farnesyl pyrophosphate (FPP). This effect was observed throughout the time course of MC3T3-E1 pre-osteoblast differentiation. Interestingly, DGBP treatment led to activation of the glucocorticoid receptor in MC3T3-E1 pre-osteoblast cells, consistent with recent findings that FPP activates nuclear hormone receptors. These findings demonstrate that direct inhibition of GGPPS, and the resulting specific depletion of GGPP, does not stimulate osteoblast differentiation. This suggests that in addition to depletion of GGPP, statin-stimulated osteoblast differentiation may depend on the depletion of upstream isoprenoids, including FPP.

AB - Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. These effects have been attributed to the depletion of geranylgeranyl pyrophosphate (GGPP). In this study, we tested whether specific inhibition of GGPP synthase (GGPPS) with digeranyl bisphosphonate (DGBP) would similarly lead to increased osteoblast differentiation. DGBP concentration dependently decreased intracellular GGPP levels in MC3T3-E1 pre-osteoblasts and primary rat calvarial osteoblasts, leading to impaired Rap1a geranylgeranylation. In contrast to our hypothesis, 1 μM DGBP inhibited matrix mineralization in the MC3T3-E1 pre-osteoblasts. Consistent with this, DGBP inhibited the expression of alkaline phosphatase and osteocalcin in primary osteoblasts. By inhibiting GGPPS, DGBP caused an accumulation of the GGPPS substrate farnesyl pyrophosphate (FPP). This effect was observed throughout the time course of MC3T3-E1 pre-osteoblast differentiation. Interestingly, DGBP treatment led to activation of the glucocorticoid receptor in MC3T3-E1 pre-osteoblast cells, consistent with recent findings that FPP activates nuclear hormone receptors. These findings demonstrate that direct inhibition of GGPPS, and the resulting specific depletion of GGPP, does not stimulate osteoblast differentiation. This suggests that in addition to depletion of GGPP, statin-stimulated osteoblast differentiation may depend on the depletion of upstream isoprenoids, including FPP.

UR - http://www.scopus.com/inward/record.url?scp=79954557143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79954557143&partnerID=8YFLogxK

U2 - 10.1002/jcb.23087

DO - 10.1002/jcb.23087

M3 - Article

C2 - 21503955

AN - SCOPUS:79954557143

VL - 112

SP - 1506

EP - 1513

JO - Journal of Cellular Biochemistry

JF - Journal of Cellular Biochemistry

SN - 0730-2312

IS - 6

ER -