Inhibitory effects of mevastatin and a geranylgeranyl transferase I inhibitor (GGTI-2166) on mononuclear osteoclast formation induced by receptor activator of NFκB ligand (RANKL) or tumor necrosis factor-α (TNF-α)

Je Tae Woo, Hiroshi Nakagawa, Annette M. Krecic, Kazuo Nagai, Andrew Hamilton, Said M. Sebti, Paula H. Stern

Research output: Contribution to journalArticle

Abstract

We have previously reported that the statin mevastatin (compactin) reversibly inhibits the fusion of TRAP-positive mononuclear preosteoclasts (pOCs) into multinucleated osteoclasts and disrupts the actin ring in mature osteoclasts through the inhibition of protein prenylation. Protein geranylgeranylation, specifically, is known to be required for pOC fusion and for the function and survival of mature osteoclasts. However, it has not been determined whether protein geranylgeranylation is involved in early differentiation of osteoclasts (pOC formation). The current study shows that statins and the geranylgeranyl transferase I inhibitor GGTI-2166 inhibit the pOC formation induced by RANKL or TNF-α in cultures of both mouse marrow-derived macrophage-colony-stimulating factor (M-CSF) dependent monocytes (MD cells) and the mouse monocyte cell line RAW 264.7 (RAW cells). Mevastatin, 0.1-0.6 μM, inhibited the formation of pOCs induced by receptor activator of nuclear factor-κB ligand (RANKL) or tumor necrosis factor (TNF-α) in both cell cultures. The inhibitory effects of mevastatin were overcome by the addition of mevalonate, farnesyl pyrophosphate or geranylgeranyl pyrophosphate. GGTI-2166 inhibited TRAP activity induced by RANKL or TNF-α in both cell cultures and prevented the incorporation of [ 3H]all-trans geranylgeraniol into prenylated proteins in RAW cells. However, the farnesyl transferase inhibitor FTI-2153 did not inhibit TRAP activity although FTI prevented the incorporation of [ 14C]mevalonate into farnesylated proteins in RAW cells. Clostridium difficile cytotoxin B (toxin B) inhibited pOC formation induced by RANKL or TNF-α in both cell cultures. The inhibitory effects of statins and GGTI-2166 on pOC formation may result from the inhibition of the geranylgeranylation of G-proteins, such as Rho or Rac, suggesting that the geranylgeranylation of these proteins is involved in the early differentiation of progenitor cells into pOCs.

Original languageEnglish (US)
Pages (from-to)87-95
Number of pages9
JournalBiochemical Pharmacology
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2005

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Protein Prenylation
Osteoclasts
Transferases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Tumor Necrosis Factor-alpha
Ligands
Cell Culture Techniques
Cell culture
Monocytes
Mevalonic Acid
Proteins
Prenylation
Macrophage Colony-Stimulating Factor
Cytotoxins
Fusion reactions
Cytoplasmic and Nuclear Receptors
GTP-Binding Proteins
Actins
Clostridium
Stem Cells

Keywords

  • FTI
  • Geranylgeranylation
  • GGTI
  • Osteoclast differentiation
  • Small G-protein
  • Statin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibitory effects of mevastatin and a geranylgeranyl transferase I inhibitor (GGTI-2166) on mononuclear osteoclast formation induced by receptor activator of NFκB ligand (RANKL) or tumor necrosis factor-α (TNF-α). / Woo, Je Tae; Nakagawa, Hiroshi; Krecic, Annette M.; Nagai, Kazuo; Hamilton, Andrew; Sebti, Said M.; Stern, Paula H.

In: Biochemical Pharmacology, Vol. 69, No. 1, 01.01.2005, p. 87-95.

Research output: Contribution to journalArticle

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AU - Woo, Je Tae

AU - Nakagawa, Hiroshi

AU - Krecic, Annette M.

AU - Nagai, Kazuo

AU - Hamilton, Andrew

AU - Sebti, Said M.

AU - Stern, Paula H.

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AB - We have previously reported that the statin mevastatin (compactin) reversibly inhibits the fusion of TRAP-positive mononuclear preosteoclasts (pOCs) into multinucleated osteoclasts and disrupts the actin ring in mature osteoclasts through the inhibition of protein prenylation. Protein geranylgeranylation, specifically, is known to be required for pOC fusion and for the function and survival of mature osteoclasts. However, it has not been determined whether protein geranylgeranylation is involved in early differentiation of osteoclasts (pOC formation). The current study shows that statins and the geranylgeranyl transferase I inhibitor GGTI-2166 inhibit the pOC formation induced by RANKL or TNF-α in cultures of both mouse marrow-derived macrophage-colony-stimulating factor (M-CSF) dependent monocytes (MD cells) and the mouse monocyte cell line RAW 264.7 (RAW cells). Mevastatin, 0.1-0.6 μM, inhibited the formation of pOCs induced by receptor activator of nuclear factor-κB ligand (RANKL) or tumor necrosis factor (TNF-α) in both cell cultures. The inhibitory effects of mevastatin were overcome by the addition of mevalonate, farnesyl pyrophosphate or geranylgeranyl pyrophosphate. GGTI-2166 inhibited TRAP activity induced by RANKL or TNF-α in both cell cultures and prevented the incorporation of [ 3H]all-trans geranylgeraniol into prenylated proteins in RAW cells. However, the farnesyl transferase inhibitor FTI-2153 did not inhibit TRAP activity although FTI prevented the incorporation of [ 14C]mevalonate into farnesylated proteins in RAW cells. Clostridium difficile cytotoxin B (toxin B) inhibited pOC formation induced by RANKL or TNF-α in both cell cultures. The inhibitory effects of statins and GGTI-2166 on pOC formation may result from the inhibition of the geranylgeranylation of G-proteins, such as Rho or Rac, suggesting that the geranylgeranylation of these proteins is involved in the early differentiation of progenitor cells into pOCs.

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