Geranylgeraniol increased mineralization in osteoblasts treated with low concentration of alendronate: A preliminary study
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Abstract
Objective: To investigate the effects of geranylgeraniol (GGOH) on alendronate (ALN)-treated osteoblast viability and bone nodule formation.
Materials and methods: MC3T3, murine osteoblast precursors, were cultured with ALN (0 and 1 µM) and GGOH (0, 10, and 50 µM). The viability of MC3T3 was determined by MTT assay at 3 and 6 days. After 3 weeks, bone nodule formation was evaluated by alizarin red S assay.
Results: Addition of ALN did not affect cell viability of MC3T3 at 3 and 6 day incubation. Bone nodule formation of ALN-treated osteoblasts exhibited lower red staining compared with that of untreated control. In the presence of ALN, there was no significant difference on viability between cells treated with GGOH and those without GGOH for 3 and 6 days. On the contrary, GGOH addition significantly increased the percentage of bone nodule formation in osteoblasts treated with ALN.
Conclusion: Low concentration of ALN reduced bone nodule formation produced by osteoblasts. Exogenous GGOH could reverse the inhibitory effect of ALN. Thus, GGOH could be a potential therapy for the conditions caused by the reduction in bone formation such as bisphosphonate-related osteonecrosis of the jaw and atypical fracture of femoral diaphysis.
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Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000 Jan; 373: 231-41.
Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006 May; 38: 617-27.
Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991 Dec; 88: 2095-105.
Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov; 333: 1437-43.
Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A. 1999 Jan; 96: 133-8.
van beek E, Lowik C, van der Pluijm G, Papapoulos S. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res. 1999 May; 14: 722-9.
Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005 Mar; 90: 1294-301.
Patntirapong S, Singhatanadgit W, Arphavasin S. Alendronate-induced atypical bone fracture: evidence that the drug inhibits osteogenesis. J Clin Pharm Ther. 2014 Aug; 39: 349-53.
Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008 Mar; 358: 1304-6.
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003 Sep; 61: 1115-7.
Idris AI, Rojas J, Greig IR, Van't Hof RJ, Ralston SH. Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int. 2008 Mar; 82: 191-201.
Manzano-Moreno FJ, Ramos-Torrecillas J, De Luna-Bertos E, Ruiz C, Garcia-Martinez O. High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis. J Craniomaxillofac Surg. 2015 Apr; 43: 396-401.
Ho HJ, Shirakawa H, Giriwono PE, Ito A, Komai M. A novel function of geranylgeraniol in regulating testosterone production. Biosci Biotechnol Biochem. 2018 Jun; 82: 956-62.
Tokuhiro K, Muramatsu M, Ohto C, Kawaguchi T, Obata S, Muramoto N, et al. Overproduction of geranylgeraniol by metabolically engineered Saccharomyces cerevisiae. Appl Environ Microbiol. 2009 Sep; 75: 5536-43.
Crick DC, Andres DA, Waechter CJ. Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem Biophys Res Commun. 1997 Aug 28; 237: 483-7.
Wang D, Christensen K, Chawla K, Xiao G, Krebsbach PH, Franceschi RT. Isolation and characterization of MC3T3-E1 preosteoblast subclones with distinct in vitro and in vivo differentiation/mineralization potential. J Bone Miner Res. 1999 Jun; 14: 893-903.
Chae JW, Seo JW, Mahat B, Yun HY, Baek IH, Lee BY, et al. A simple pharmacokinetic model of alendronate developed using plasma concentration and urine excretion data from healthy men. Drug Dev Ind Pharm. 2014 Oct; 40 :1325-9.
Scheper MA, Badros A, Salama AR, Warburton G, Cullen KJ, Weikel DS, et al. A novel bioassay model to determine clinically significant bisphosphonate levels. Support Care Cancer. 2009 Dec; 17:1553-7.
Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS. Osteoblast proliferation and maturation by bisphosphonates. Biomaterials. 2004 Aug; 25: 4105-15.
Chang CH, Wang CZ, Chang JK, Hsu CY, Ho ML. The susceptive alendronate-treatment timing and dosage for osteogenesis enhancement in human bone marrow-derived stem cells. PLoS One. 2014; 9: e105705.
Iwata K, Li J, Follet H, Phipps RJ, Burr DB. Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia. Bone. 2006 Nov; 39: 1053-8.
Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE. Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res. 2009 Oct; 24: 1736-40.
Zafar S, Coates DE, Cullinan MP, Drummond BK, Milne T, Seymour GJ. Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts. Clin Oral Investig. 2016 Nov; 20: 2023-35.