Effect of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages

Bisphosphonates (BP) are powerful inhibitors of bone resorption. Their mechanism of action, although still unclear, is now believed to be at the cellular level. In this study we investigated the effects of these compounds on proliferation, induced either by L-cell conditioned medium (CSF-1) or 4-phorbol 12-myristate 13-acetate (PMA) of bone marrow cells (BMC) and on CSF-1-induced proliferation and viability of bone marrow derived macrophages (BMDM phi). BMC proliferation, measured by [3H]-TdR incorporation or by clonal assay in soft agar, was significantly inhibited by 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) and 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP) at 2.5 x 10(-7) M and by dichloromethylenebisphosphonate (Cl2MBP) at 2.5 x 10(-6) M. This inhibitory effect was also confirmed on the proliferation, measured by [3H]-TdR incorporation, of BMDM phi. In the absence of CSF-1, the viability of this latter cell population, estimated by DNA content per well and lactate dehydrogenase (LDH) released into the medium, was affected in the following order of concentrations: Cl2MBP, 1.0 x 10(-4) M; AHBuBP, 5.0 x 10(-5) M; and AHPrBP, 2.5 x 10(-5) M. Since osteoclasts and macrophages might share a common early progenitor cell, probably under the control of CSF-1, the effect exerted by BP on the proliferation of the macrophage precursors may also be extended to the osteoclast precursors.