Lactoferrin potently inhibits osteoblast apoptosis, via an LRP1-independent pathway

Lactoferrin induces osteoblast proliferation in vitro and is anabolic to bone in vivo. We recently reported that the low-density lipoprotein-receptor-related protein 1 (LRP1), a multifunctional member of the LDL receptor family, transduces the mitogenic signal activated by lactoferrin. Here we investigate the effects of lactoferrin on osteoblast survival. At periphysiological concentrations (1-10mug/ml), lactoferrin protects both primary rat osteoblastic cells and SaOS2 cells from apoptosis induced by serum withdrawal. Surprisingly, this effect was not sensitive to the LRP1/2 inhibitor receptor-associated protein (RAP). Neither did lactoferrin selectively prevent apoptosis in fibroblastic cells expressing wild-type LRP1 compared to LRP1-null fibroblasts. Lactoferrin activates PI3 kinase-dependent Akt signaling in osteoblasts but this effect is neither LRP1-dependent nor required for lactoferrin-induced cell survival. Lactoferrin activates p42/44 MAPK signaling, but inhibiting this process does not abrogate its pro-survival actions. These results demonstrate that lactoferrin promotes osteoblast survival, an effect that may contribute to its anabolic skeletal actions in vivo. Our data also suggest that the molecular mechanisms that underpin the ability of lactoferrin to promote cell survival differ fundamentally from those which subserve its mitogenic actions, in particular being mediated by a distinct cell-membrane-based receptor.