title: Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition.
abstract: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid metabolites as therapeutic agents for BRONJ.
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nagaoka
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan kajiya@college.fdcnet.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Kajiya
authors.affiliation: Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ozeki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikebe
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Okabe
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D056657:Cathepsin K / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008437:Maxilla / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D018003:Receptors, Calcitonin / Q000187:drug effects; D012475:Salmonella; D000071681:Tartrate-Resistant Acid Phosphatase; D020390:Tooth Socket / Q000187:drug effects; D025262:Vacuolar Proton-Translocating ATPases / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004224:Diterpenes; D007093:Imidazoles; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C527519:OC-STAMP protein, mouse; D011106:Polyisoprenyl Phosphates; D018003:Receptors, Calcitonin; D005204:Farnesol; D000077211:Zoledronic Acid; C040155:geranylgeranic acid; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
keywords: DC-STAMP; bone remodeling; geranylgeranyl pyrophosphate; oral surgery; osteoclasts; osteonecrosis