title: A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and ovariectomy-induced bone loss in vivo.
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 muM) 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.
authors.affiliation: Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK. a.hughes@abdn.ac.uk
authors.forename: Alun
authors.initials: A
authors.lastname: Hughes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.forename: Aymen I
authors.initials: AI
authors.lastname: Idris
authors.forename: Julie C
authors.initials: JC
authors.lastname: Crockett
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010052:Ovariectomy; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use; D017368:Protein Prenylation / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D014867:Water / Q000737:chemistry; D020827:rap1 GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D014867:Water; D019821:Simvastatin; C086276:cerivastatin; D020827:rap1 GTP-Binding Proteins; D017035:Pravastatin