Compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts.
Compactin (mevastatin), which inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and thus biosynthesis of cholesterol and the prenylation of proteins, inhibits osteoclastic bone resorption. Although it has been suggested that compactin inhibits bone resorption by inducing apoptosis of osteoclasts, the pathway by which compactin inhibits resorption has not been established. We investigated the effect of compactin on the differentiation of osteoclasts and the relationship between the morphological changes elicited by compactin and its inhibitory effect on bone resorption. Compactin inhibited the differentiation of osteoclasts, interfering with the fusion process by which prefusion osteoclasts (pOCs) develop into multinucleated osteoclast-like cells (OCLs), and also disrupted the actin ring of OCLs. The potency of compactin to inhibit fusion of pOCs and to disrupt the actin ring of OCLs corresponded to that of compactin to inhibit bone resorption. The effects of compactin were prevented by the addition of MVA lactone or its downstream products farnesylpyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP) but not by squalene. Apoptosis of OCLs was not induced by the concentration of compactin that inhibited fusion of pOCs and disrupted the actin ring. The normal process of pOC fusion and the integrity of the actin ring were restored by the withdrawal of compactin from the cultures after they had been treated with compactin for 24 h, but they were not restored by the addition of zVAD-fmk, a caspase inhibitor. Compactin also reversibly inhibited interleukin-1beta (IL-1beta)-, 1alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3)-, and parathyroid hormone (PTH)-stimulated 45Ca release in bone organ cultures. Our results indicate that the inhibitory effects of compactin on bone resorption result from the inhibition of fusion of pOCs into OCLs and disruption of actin ring in OCLs and that apoptosis of OCLs is not necessary for these inhibitory effects of compactin. These effects of compactin are likely to be a consequence of the inhibition of prenylation of proteins that play an important role in the fusion of pOCs and in maintaining actin ring integrity in OCLs.
Woo
J T
JT
Department of Bioengineering, Tokyo Institute of Technology, Yokohama, Japan.
Kasai
S
S
Stern
P H
PH
Nagai
K
K
D000199:Actins / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001862:Bone Resorption / Q000503:physiopathology*; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018920:Coculture Techniques; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects*; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012717:Sesquiterpenes
D000199:Actins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D010281:Parathyroid Hormone; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C012258:mevastatin; C004808:farnesyl pyrophosphate; D008148:Lovastatin; D002117:Calcitriol; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid; D002118:Calcium