Abstract
Osteoclast differentiation is a complex process involving cytoskeleton and nuclear reorganization. Osteoclasts regulate bone homeostasis and have a key role in bone degenerative processes. Osteolysis and osteoporosis characterize a subset of laminopathies, inherited disorders due to defects in lamin A/C. Laminopathies featuring bone resorption are characterized, at the molecular level, by anomalous accumulation of the unprocessed lamin A precursor, called prelamin A. To obtain a suitable cell model to study prelamin A effects on osteoclasts, prelamin A processing inhibitors FTIโ277 or AFCMe were applied to peripheral blood monocytes induced to differentiate towards the osteoclastic lineage. Previous studies have shown that treatment with FTIโ277 causes accumulation of nonโfarnesylated prelamin A, while AFCMe inhibition of prelamin A maturation causes accumulation of a farnesylated form. We demonstrate that monocytes subjected to FTIโ277 treatment and mostly those subjected to AFCMe administration, differentiate towards the osteoclastic lineage more efficiently than untreated monocytes, in terms of number of multinucleated giant cells, mRNA expression of osteoclastโrelated genes and TRACP 5b activity. On the other hand, the bone resorption activity of osteoclasts obtained in the presence of high prelamin A levels is lower with respect to control osteoclasts. This finding may help the understanding of the osteolytic and osteoporotic processes that characterize progeroid laminopathies. J. Cell. Biochem. 105: 34โ40, 2008. ยฉ 2008 WileyโLiss, Inc.