Bone remodeling, the turnover of bone, is highly regulated by several pathways, including the regulatory loops between osteoblasts and osteoclasts. We investigated the role of galectin-8, a b-galactoside mammalian lectin, on osteoclast and osteoblast differentiation. We found that galectin-8 plays a previously unknown role in bone remodeling that involves osteoclast activation, mediated by osteoblast production of RANKL. The elevation in RANKL induced by galectin-8 is dependent upon activation of the MEK/ERK pathway in osteoblasts. Galectin-8 was found to suppress expression of OPG, the decoy receptor of RANKL. In longer treatment times (4-6 days) galectin-8 was found to attenuate its ability to activate osteoclasts, as a mechanism of feedback control. Further, galectin-8 suppresses osteoblast differentiation by inhibiting expression of osterix, a mandatory transcription factor needed for this process. Accordingly, mice over-expressing galectin-8, which were generated in our lab, were found to be osteopenic, with a distinct reduction in bone mass and mineral density, due to elevated activation of osteoclasts in their bone marrow. This was a result of both higher expression of RANKL and lower expression of osterix in osteoblasts. Furthermore, knock-out mice to galectin-8 were osteosclerotic, showing increased bone mass and mineral density, which was accompanied by reduction in active osteoclasts and RANKL production in osteoblasts. Taken together our results reveal that galectin-8 is a new player in bone remodeling, acting to support bone resorption. This may have several implications in the physiological maintenance of proper bone homeostasis, as well as in pathological cases such as bone metastasis of prostate cancer cells that secrete galectin-8.
