G Duque1, C Vidal, D Rivas. 1. Ageing Bone Research Program, Sydney Medical School - Nepean Campus, The University of Sydney, Penrith, NSW, Australia. gustavo.duque@sydney.edu.au
Abstract
BACKGROUND AND PURPOSE: Protein isoprenylation is an important step in the intracellular signalling pathway conducting cell growth and differentiation. In bone, protein isoprenylation is required for osteoclast differentiation and activation. However, its role in osteoblast differentiation and function remains unknown. In this study, we assessed the role of protein isoprenylation in osteoblastogenesis in a model of mesenchymal stem cells (MSC) differentiation. EXPERIMENTAL APPROACH: We tested the effect of an inhibitor of farnesylation [farnesyl transferase inhibitor-277 (FTI-277)] and one of geranylgeranylation [geranylgeranyltransferase inhibitor-298 (GGTI-298)] on osteoblast differentiating MSC. In addition, we tested the effect of alendronate on protein isoprenylation in this model either alone or in combination with other inhibitors of isoprenylation. KEY RESULTS: Initially, we found that levels of unfarnesylated proteins (prelamin A and HDJ-2) increased after treatment with FTI-277 concomitantly affecting osteoblastogenesis and increasing nuclear morphological changes without affecting cell survival. Furthermore, inhibition of geranylgeranylation by GGTI-298 alone increased osteoblastogenesis. This effect was enhanced by the combination of GGTI-298 and alendronate in the osteogenic media. CONCLUSIONS AND IMPLICATIONS: Our data indicate that both farnesylation and geranylgeranylation play a role in osteoblastogenesis. In addition, a new mechanism of action for alendronate on protein isoprenylation in osteogenic differentiating MSC in vitro was found. In conclusion, protein isoprenylation is an important component of the osteoblast differentiation process that could constitute a new therapeutic target for osteoporosis in the future.
BACKGROUND AND PURPOSE: Protein isoprenylation is an important step in the intracellular signalling pathway conducting cell growth and differentiation. In bone, protein isoprenylation is required for osteoclast differentiation and activation. However, its role in osteoblast differentiation and function remains unknown. In this study, we assessed the role of protein isoprenylation in osteoblastogenesis in a model of mesenchymal stem cells (MSC) differentiation. EXPERIMENTAL APPROACH: We tested the effect of an inhibitor of farnesylation [farnesyl transferase inhibitor-277 (FTI-277)] and one of geranylgeranylation [geranylgeranyltransferase inhibitor-298 (GGTI-298)] on osteoblast differentiating MSC. In addition, we tested the effect of alendronate on protein isoprenylation in this model either alone or in combination with other inhibitors of isoprenylation. KEY RESULTS: Initially, we found that levels of unfarnesylated proteins (prelamin A and HDJ-2) increased after treatment with FTI-277 concomitantly affecting osteoblastogenesis and increasing nuclear morphological changes without affecting cell survival. Furthermore, inhibition of geranylgeranylation by GGTI-298 alone increased osteoblastogenesis. This effect was enhanced by the combination of GGTI-298 and alendronate in the osteogenic media. CONCLUSIONS AND IMPLICATIONS: Our data indicate that both farnesylation and geranylgeranylation play a role in osteoblastogenesis. In addition, a new mechanism of action for alendronate on protein isoprenylation in osteogenic differentiating MSC in vitro was found. In conclusion, protein isoprenylation is an important component of the osteoblast differentiation process that could constitute a new therapeutic target for osteoporosis in the future.
Authors: F P Coxon; M H Helfrich; R Van't Hof; S Sebti; S H Ralston; A Hamilton; M J Rogers Journal: J Bone Miner Res Date: 2000-08 Impact factor: 6.741
Authors: Brian C Capell; Michael R Erdos; James P Madigan; James J Fiordalisi; Renee Varga; Karen N Conneely; Leslie B Gordon; Channing J Der; Adrienne D Cox; Francis S Collins Journal: Proc Natl Acad Sci U S A Date: 2005-08-29 Impact factor: 11.205
Authors: Aryeh M Abeles; Nada Marjanovic; Jean Park; Mukundan Attur; Edwin S Chan; Hayf E Al-Mussawir; Hayfez Al-Mussawir; Mandar Dave; Mark C Fisher; Steven A Stuchin; Steven B Abramson; Michael H Pillinger Journal: Arthritis Rheum Date: 2007-09
Authors: Juan Carlos Cardet; Xiaofeng Jiang; Quan Lu; Norma Gerard; Kristen McIntire; Homer A Boushey; Mario Castro; Vernon M Chinchilli; Christopher D Codispoti; Anne-Marie Dyer; Fernando Holguin; Monica Kraft; Stephen Lazarus; Robert F Lemanske; Njira Lugogo; Dave Mauger; Wendy C Moore; James Moy; Victor E Ortega; Stephen P Peters; Lewis J Smith; Julian Solway; Christine A Sorkness; Kaharu Sumino; Michael E Wechsler; Sally Wenzel; Elliot Israel Journal: J Allergy Clin Immunol Date: 2019-03-11 Impact factor: 10.793
Authors: Behzad Yeganeh; Emilia Wiechec; Sudharsana R Ande; Pawan Sharma; Adel Rezaei Moghadam; Martin Post; Darren H Freed; Mohammad Hashemi; Shahla Shojaei; Amir A Zeki; Saeid Ghavami Journal: Pharmacol Ther Date: 2014-02-26 Impact factor: 12.310
Authors: Wei Li; Li Sze Yeo; Christopher Vidal; Thomas McCorquodale; Markus Herrmann; Diane Fatkin; Gustavo Duque Journal: PLoS One Date: 2011-04-25 Impact factor: 3.240
Authors: Arvind Ponnusamy; Smeeta Sinha; Gareth D Hyde; Samantha J Borland; Rebecca F Taylor; Emma Pond; Heather J Eyre; Colette A Inkson; Andrew Gilmore; Nick Ashton; Philip A Kalra; Ann E Canfield Journal: PLoS One Date: 2018-04-24 Impact factor: 3.240