Bone loss is a common feature of several chronic inflammatory and autoimmune diseases and the risk of osteoporosis is increased in patients with rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. Hyperactivation of osteoclasts (OCs) is a feature of several autoimmune diseases, cancers, and infections1,2. ICOS-L is the ligand of the ICOS T cell costimulatory molecule, and it is expressed in haematopoietic e non-haematopoietic cells. Recent reports showed that the ICOS-L:ICOS interaction may trigger bidirectional signals which are able to modulate the response of both the cells expressing ICOS and those expressing ICOS-L3,4. This work stems from our finding that OCs can express ICOS-L, and it was aimed to investigate the effect of ICOS-L triggering on differentiation and function of OCs in vitro and in vivo. METHODS: We analyzed the effect of ICOS-L triggering using recombinant ICOS-Fc in 1) OCs obtained by culturing human CD14+ monocytes in the presence of M-CSF and RANKL in vitro, and 2) in two mouse model of osteoporosis in vivo. RESULTS: The in vitro results showed that ICOS-L triggering reversibly inhibits OCs differentiation in terms of acquirement of the OCs morphology and the CD14-Cathepsin K+TRAP+ phenotype. Moreover, it decreases the size of cells and nuclei, the expression of specific OCs markers, and ability to promote calcium release. A similar effect was detected on already differentiated OCs. The in vivo results showed that mouse treatment with ICOS-Fc strikingly inhibits the systemic bone resorption in osteoporosis induced by either treatment with soluble RANKL5 or ovariectomy. DISCUSSION: ICOS-L is expressed in OCs and its triggering by ICOS inhibits OCs function both in vitro and in vivo. CONCLUSION: This work describes a novel immunologic mechanism controlling bone resorption and opens a novel field in the pharmacological use of agonists and antagonists of the ICOS/B7h system.
ICOS-Ligand triggering impairs osteoclast differentiation in vitro and in vivo.
DIANZANI, Chiara;
2016-01-01
Abstract
Bone loss is a common feature of several chronic inflammatory and autoimmune diseases and the risk of osteoporosis is increased in patients with rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. Hyperactivation of osteoclasts (OCs) is a feature of several autoimmune diseases, cancers, and infections1,2. ICOS-L is the ligand of the ICOS T cell costimulatory molecule, and it is expressed in haematopoietic e non-haematopoietic cells. Recent reports showed that the ICOS-L:ICOS interaction may trigger bidirectional signals which are able to modulate the response of both the cells expressing ICOS and those expressing ICOS-L3,4. This work stems from our finding that OCs can express ICOS-L, and it was aimed to investigate the effect of ICOS-L triggering on differentiation and function of OCs in vitro and in vivo. METHODS: We analyzed the effect of ICOS-L triggering using recombinant ICOS-Fc in 1) OCs obtained by culturing human CD14+ monocytes in the presence of M-CSF and RANKL in vitro, and 2) in two mouse model of osteoporosis in vivo. RESULTS: The in vitro results showed that ICOS-L triggering reversibly inhibits OCs differentiation in terms of acquirement of the OCs morphology and the CD14-Cathepsin K+TRAP+ phenotype. Moreover, it decreases the size of cells and nuclei, the expression of specific OCs markers, and ability to promote calcium release. A similar effect was detected on already differentiated OCs. The in vivo results showed that mouse treatment with ICOS-Fc strikingly inhibits the systemic bone resorption in osteoporosis induced by either treatment with soluble RANKL5 or ovariectomy. DISCUSSION: ICOS-L is expressed in OCs and its triggering by ICOS inhibits OCs function both in vitro and in vivo. CONCLUSION: This work describes a novel immunologic mechanism controlling bone resorption and opens a novel field in the pharmacological use of agonists and antagonists of the ICOS/B7h system.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
