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
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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
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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
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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
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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
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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
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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
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