20/07/2009 OsteoImmunology Interplay between the Immune System and Bone The Osteoclast Lymphocyte Macrophage Anna Teti Osteoclasts Department of Experimental Medicine University of L’Aquila Osteoblasts Osteoblasts Italy Bone Osteocytes Interplay between the Immune System and Bone •Osteoblasts influence haematopoiesis •Osteoclasts originate from myeloid precursors •Immune system regulates bone cell actvity Osteoblasts Influence Lymphocyte Macrophage Haematopoiesis Osteoclasts Osteoblasts Osteoblasts Bone Osteocytes Bone/Bone Marrow Organ Bone Marrow Array Bone Osteoblasts Bone Marrow 1 20/07/2009 Haematopoiesis Haematopoiesis Bone Stem Immature Mature Stem Cell Niches Osteoblast Niche Quiscent Bone G0 SNO Detachment from the Osteoblast Niche Endosteal Osteoblasts Osteoblast-Stem Cell Stem Cell Niches 2 20/07/2009 Osteoclasts Osteoclasts Originate from Myeloid Precursors Osteoclasts Osteoclasts Bone Remodelling • Multinucleated cells • Resorb the inorganic and organic bone matrix Osteoblasts • Contribute to the Osteoclasts regulation of Ca 2+ homeostasis Newly formed bone • Regulate osteoblast activity Bone Resorption Osteoclast Precursors M-CSF M-CSF Teitelbaum and Ross, 2003 Walsh et al., 2006 3 20/07/2009 Osteoclast Origin RANK-RANKL-OPG Axis • RANK – Receptor Activator of Nuclear Factor –κB • TNF-Receptor superfamily member – Expressed by the osteoclast lineage • RANKL (TRANCE, ODF) – RANK Ligand • TNF superfamily member – Expressed by the osteoblast lineage – Activated lymphocytes Teitelbaum and Ross, 2003 – Synovial fibroblasts • OPG – Osteoprotegerin • Decoy RANKL receptor – Expressed by the osteoblast lineage RANK-RANKL-OPG Axis RANK-RANKL-OPG Axis RANKL OPG Osteoclast RANK Osteoblast Signal XSignal mRANKL sRANKL RANK OPG RANKL/OPG Ratio 1.0 200 CONTROL ON GFD ** * Immune System Regulates NOT ON GFD 0.8 150 ** ** Bone Cell Activity 0.6 100 ** * 0.4 50 RANKL/OPG 0 0.2 N. MULTINUCLEATED TRAP-POSITIVE CELLS TRAP-POSITIVEN. MULTINUCLEATED 0.0 1 2 3 CONTROL ON-GFD NOT ON GFD WEEKS 4 20/07/2009 RANK-RANKL Signal RANK-RANKL Signal Takayanagi, 2005 Takayanagi, 2005 Interferon Signal Interplay with Immune System Takayanagi et al, 2002 Takayanagi, 2006 Increased Osteoclast Activity Interplay with Immune System in Inflammatory Diseases Ritchlin et al, 2003 Takayanagi, 2006 5 20/07/2009 Cytokine Receptors IL-6 Teitelbaum, 2006 IL-6 Increases Impact of IL-6 on Osteoblasts Osteoclastogenesis OB OB OC OCp OCp OC WT IL6-TG WT IL6-TG De Benedetti et al, Arthritis & Rheum, 2006 De Benedetti et al, Arthritis & Rheum, 2006 IL-6 Impairs Interplay with Immune System Somatic Growth WT IL6- TG WT IL6- TG De Benedetti et al, Arthritis & Rheum, 2006 Takayanagi, 2006 6 20/07/2009 ITAM Co-Receptors DAP12/FcR γ Co-Receptors Immunoreceptor Tyrosine-based Activation Motif (ITAM) adaptors Takayanagi, 2005 Takayanagi, 2005 Conclusions Bone Remodelling • An interplay exists between bone and the immune system Lymphocyte Macrophage • Osteoblasts influence the immune system Osteoclasts • The immune system regulates bone cell function Osteoblasts • Osteoclasts are likely to belong to the X X immune system cell family Osteocytes 7.