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Protein isoprenylation regulates osteogenic differentiation of mesenchymal stem cells: effect of alendronate, and farnesyl and geranylgeranyl transferase inhibitors
Author(s) -
Duque G,
Vidal C,
Rivas D
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01111.x
Subject(s) - prenylation , geranylgeranylation , osteoblast , mesenchymal stem cell , osteoclast , microbiology and biotechnology , cellular differentiation , protein kinase a , geranylgeranyl pyrophosphate , biology , kinase , chemistry , biochemistry , in vitro , enzyme , gene
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.