Lithium inhibits calcitriol-stimulated formation of multinucleated cells in human long-term marrow cultures

We observed that lithium (3 mM) blocked the 1,25-dihydroxyvitamin D [1,25-(OH)2D3]-stimulated bone resorption in fetal rat long bones in culture. Because this inhibitory effect was not seen when bone resorption was stimulated by parathyroid hormone or interleukin-1, we reasoned that Li specifically inhibited events involved in the 1,25-(OH)D3-stimulated bone resorption. The increased bone resorption induced by vitamin D in culture is associated with differentiation and/or fusion of osteoclast progenitors. In the present work, we studied the effect of Li on the basal and 1,25-(OH)2D3-stimulated generation of multinucleated osteoclast-like cells (MNC) and MNC containing tartrate-resistant acid phosphatase (TRAP+) in long-term human bone marrow cultures. Total MNC and TRAP+ cells were counted after 3 weeks of culture. In the absence of both lithium and 1,25-(OH)2D3, total MNC and TRAP+ cell numbers were 146 ± 22 and 110 ± 18 per well, respectively (mean ± SEM); in the presence of Li, corresponding figures were 79 ± 17 and 59 ± 14. When the generation of MNC and TRAP+ cells was stimulated with 1,25-(OH)2D3, (10−8 M), total MNC and TRAP+ cells were 521 ± 66 and 473 ± 63, respectively, in the absence of Li and 251 ± 44 and 155 ± 27 in the presence of Li (p < 0.05). The inhibitory effect of Li was dose dependent and was not observed when the cultures were exposed to parathyroid hormone instead of 1,25-(OH)2D3. When Li was added to the cells the first week of culture only, we observed the full inhibitory effect; conversely, if Li was added for the last week of culture only, no inhibitory effect was seen. These data show that Li interferes with the recruitment of osteoclast-like cells from their precursors, probably at an early stage of differentiation.