A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and ovariectomy-induced bone loss in vivo

Alun Hughes, Michael J. Rogers, Aymen I. Idris, Julie C. Crockett

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Statins potently inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, blocking downstream biosynthesis of isoprenoid lipids and causing inhibition of protein prenylation. Prenylated signaling molecules are essential for osteoclast function, consistent with our previous observation that mevastatin can inhibit osteoclast activity in vitro. Several reports suggest that statins may also have an anabolic effect on bone and stimulate osteoblast differentiation. This study sought to determine the effects of both hydrophobic and hydrophilic statins, particularly rosuvastatin (RSV), on osteoclast function in vitro and in vivo. All statins tested (RSV, pravastatin [PRA], cerivastatin [CER], and simvastatin [SIM]) caused accumulation of unprenylated Rap-1A in rabbit osteoclast-like cells and J774 macrophages in vitro and inhibited osteoclast-mediated resorption. The order of potency for inhibiting prenylation in vitro (at concentrations of 0.01-50 mu M) was CER > SIM > RSV > PRA. The most potent hydrophilic statin (CER, 0.05 and 0.3 mg/kg) inhibited prenylation in rabbit osteoclasts 24 hours after a single subcutaneous (s.c.) injection more effectively than the most potent hydrophobic statin (RSV, 20 mg/kg). However, in a mouse model of osteoporosis, s.c. 0.05 mg/kg/day CER and 2 or 20 mg/kg/day RSV for 3 weeks only mildly prevented loss of cortical and trabecular bone induced by ovariectomy. No increase in bone formation rate was observed with statin treatment, suggesting that this effect was due to inhibition of osteoclast-mediated resorption rather than increased bone formation.

Original languageEnglish
Pages (from-to)403-413
Number of pages11
JournalCalcified Tissue International
Volume81
Issue number5
DOIs
Publication statusPublished - 2007

Keywords

  • osteoclast
  • bone resorption
  • statin
  • prenylation
  • anabolic
  • HMG-COA REDUCTASE
  • Nitrogen-containing bisphosphonates
  • randomized controlled-trial
  • mevalonate pathway
  • competitive inhibitors
  • secondary analysis
  • binding proteins
  • fracture risk
  • pravastatin
  • resorption

Cite this

A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and ovariectomy-induced bone loss in vivo. / Hughes, Alun; Rogers, Michael J.; Idris, Aymen I.; Crockett, Julie C.

In: Calcified Tissue International, Vol. 81, No. 5, 2007, p. 403-413.

Research output: Contribution to journalArticle

Hughes, Alun ; Rogers, Michael J. ; Idris, Aymen I. ; Crockett, Julie C. / A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and ovariectomy-induced bone loss in vivo. In: Calcified Tissue International. 2007 ; Vol. 81, No. 5. pp. 403-413.
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KW - mevalonate pathway

KW - competitive inhibitors

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KW - binding proteins

KW - fracture risk

KW - pravastatin

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