ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo

Abstract

Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone homeostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte-derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD14 cathepsin K phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings open a novel field in the pharmacological use of agonists and antagonists of the ICOS-B7h system.

Sr-Containing Mesoporous Bioactive Glasses Bio-Functionalized with Recombinant ICOS-Fc: An In Vitro Study

“…More in detail, ICOS is a T cell co-stimulatory surface receptor, which binds to ICOS-L, a surface receptor expressed by several cell types, including osteoclasts. Recent findings have shown that the binding ICOS:ICOS-L is involved in the regulation of bone turnover and that the administration of a soluble recombinant form of ICOS (ICOS-Fc) reversibly inhibits human osteoclast activity in vitro [25]. Moreover the authors demonstrated that the administration of ICOS-Fc in vivo is able to inhibit and possibly reverse the development of experimental osteoporosis (OP) in mice [25].…”

Osteopontin binds ICOSL promoting tumor metastasis

“…Secondly, they are involved in cell migration, which is induced by OPN and inhibited by ICOS-mediated ICOSL triggering 10 . Thirdly, they are involved in the bone metabolism, since OPN is a key bone component produced by osteoblasts, whereas ICOS-mediated triggering of ICOSL expressed by osteoclasts (OC) inhibits OC differentiation from monocytes and bone resorption activity of mature OC in vitro, and the development of osteoporosis in vivo 18 .…”

Role of endocytosis and trans-endocytosis in ICOS costimulator-induced downmodulation of the ICOS Ligand

“…17,[26][27][28][32][33][34]56,57 In normal or tumor cells of hematopoietic and non-hematopoietic origin that express ICOS-L, ICOS-L downmodulation would suppress its own signals. 20,30,31,[35][36][37] In B lymphocytes, ICOS-L downmodulation is induced by interaction with ICOS, by PKC activators, or by anti-IgM antibodies. 45 Interestingly, PKC and anti-IgM induce ICOS-L shedding and release into supernatants, that was dependent on -secretase activity.…”

“…35 Our results in monocyte-derived human DC show that ICOS-L signalling enhanced LPS-induced secretion of cytokines IL-10 and IL-23, antigen cross-presentation by class I MHC, DC adhesion to endothelial cells, or chemokine-induced migration 36 ; similar conclusions have been reached by Hedl et al 20 Interaction with ICOS also inhibited the migration of ICOS-L + non-hematopoietic cells including endothelial cells and different types of tumor cells, 30,36 the adhesion between endothelial cells and polymorphonuclear leukocytes or tumor cell lines, 31 and osteoclast differentiation. 37 The nature of ICOS-L-induced signals depends on the experimental system. So, whereas induction of IL-6 in mouse DC is dependent on the p38 MAPK, 35 ICOS-L lowers ERK activation induced by E-selectin or osteopontin.…”