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A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and
Alun Hughes1, Michael J Rogers, Aymen I Idris
1Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK. a.hughes@abdn.ac.uk
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.
Insights
Statins inhibit protein prenylation, crucial for osteoclast function, thereby reducing bone resorption. While effective in vitro, statin treatment showed only mild bone protection in an osteoporosis model, primarily via resorption inhibition.
Area of Science:
- Biochemistry
- Pharmacology
- Bone Biology
Background:
- Statins inhibit HMG-CoA reductase, impacting isoprenoid lipid biosynthesis and protein prenylation.
- Prenylated proteins are vital for osteoclast activity; statins may influence bone metabolism.
- Previous research indicated mevastatin inhibits osteoclast activity in vitro.
Purpose of the Study:
- To investigate the effects of hydrophobic and hydrophilic statins on osteoclast function.
- To evaluate rosuvastatin's impact on osteoclast activity in vitro and in vivo.
- To compare the efficacy of different statins in an osteoporosis model.
Main Methods:
- Assessed statin-induced accumulation of unprenylated Rap-1A in osteoclast-like cells and macrophages.
- Measured osteoclast-mediated bone resorption in vitro.
- Administered statins subcutaneously in a mouse model of ovariectomy-induced osteoporosis.
Main Results:
- All tested statins (rosuvastatin, pravastatin, cerivastatin, simvastatin) inhibited protein prenylation and osteoclast resorption in vitro.
- Cerivastatin demonstrated superior in vitro prenylation inhibition compared to rosuvastatin.
- In vivo, statins mildly prevented bone loss in an osteoporosis model, with no observed increase in bone formation.
Conclusions:
- Statins inhibit osteoclast function by blocking protein prenylation, leading to reduced bone resorption.
- The bone-protective effects in vivo appear to be primarily due to decreased osteoclast activity, not enhanced bone formation.
- Further research may explore optimizing statin therapy for bone health.
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