Hyperactivation of osteoclasts (OCs) can be detected in conditions such as osteoporosis, rheumatoid arthritis and other autoimmune diseases, and osteolytic tumor metastases. B7h is the ligand of the ICOS T cell costimulatory molecule, and it is expressed in haematopoietic e non-haematopoietic cells. Recent reports have shown that the B7h:ICOS interaction may trigger bidirectional signals which are able to modulate the response of both the cells expressing ICOS and those expressing B7h. This work gems from our finding that OCs (differentiated in vitro from monocytes by culture in the presence of RANKL and M-CSF) can express B7h, and it was aimed to investigate the effect of B7h triggering on differentiation and function of OCs in vitro and in vivo. The in vitro results showed that B7h triggering using ICOS-Fc (a recombinant soluble form of ICOS) reversibly inhibited OCs differentiation from monocytes in terms of acquirement of the OCs morphology (giant multinuclear cells) and the CD14-Cathepsin K+TRAP+ phenotype. Moreover, it induced reduction of the size of cells and nuclei, decreased ability to adhere to the substrate and to promote calcium release from crystalline calcium phosphate. A similar effect was detected on already differentiated OCs. The in vivo results showed that the treatment with ICOS-Fc strikingly inhibited the systemic bone resorption induced in mice by treatment with high doses of soluble RANKL, which is a mouse model of osteoporosis. Therefore, these data detected a novel molecular system involved in osteoimmunology. Moreover, they open a novel field in the pharmacological use of agonists and antagonists of the ICOS/B7h system which to date have been envisaged as immune modulators mainly in the fields of autoimmune diseases and anti-tumor immune response.
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