title: Atorvastatin stimulates the production of osteoprotegerin by human osteoblasts.
abstract: Recently, HMG-CoA reductase inhibitors (statins), potent inhibitors of cholesterol biosynthesis, have been linked to protective effects on bone metabolism. Because of their widespread use, prevention of bone loss and fractures would be a desirable side effect. However, the mechanisms how statins may affect bone metabolism are poorly defined. Here, we evaluated the effect of atorvastatin on osteoblastic production of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG), cytokines that are essential for osteoclast cell biology. While RANKL enhances osteoclast formation and activation, thereby, promoting bone loss, OPG acts as a soluble decoy receptor and antagonizes the effects of RANKL. In primary human osteoblasts (hOB), atorvastatin increased OPG mRNA levels and protein secretion by hOB by up to three fold in a dose-dependent manner with a maximum effect at 10(-6) M (P < 0.001). Time course experiments indicated a time-dependent stimulatory effect of atorvastatin on OPG mRNA levels after 24 h and on OPG protein secretion after 48-72 h (P < 0.001). Treatment of hOB with substrates of cholesterol biosynthesis that are downstream of the HMG-CoA reductase reaction (mevalonate, geranylgeranyl pyrophosphate) reversed atorvastatin-induced enhancement of OPG production. Of note, atorvastatin abrogated the inhibitory effect of glucocorticoids on OPG production. Treatment of hOB with atorvastatin enhanced the expression of osteoblastic differentiation markers, alkaline phosphatase and osteocalcin. In summary, our data suggest that atorvastatin enhances osteoblastic differentiation and production of OPG. This may contribute to the bone-sparing effects of statins.
authors.affiliation: Department of Obstetrics and Gynecology, Georg-August-University, Goettingen, Germany. viereck@med.uni-goettingen.de
authors.forename: Volker
authors.initials: V
authors.lastname: Viereck
authors.forename: Carsten
authors.initials: C
authors.lastname: Gründker
authors.forename: Sabine
authors.initials: S
authors.lastname: Blaschke
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Frosch
authors.forename: Michael
authors.initials: M
authors.lastname: Schoppet
authors.forename: Günter
authors.initials: G
authors.lastname: Emons
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000328:Adult; D000069059:Atorvastatin; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D006023:Glycoproteins; D006538:Heptanoic Acids; D053244:Osteoprotegerin; D011758:Pyrroles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; D000069059:Atorvastatin; D008798:Mevalonic Acid