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1 Tel: ; silent epidemic,. (WHO),. 5 3, %, 25%, 20% (12~35%). 2.8% 0.7% 4. ( ). bone remodeling (osteoblast), (osteoclast),.. 3~4.. 70% (osteocyte) (bone lining cell). 10. RANK/RANKL/OPG (1). RANK (Receptor-Activator of Nuclear factor Kappa B) TNF receptor family ( 1). RANKL (RANK ligand). RANKL,. RANKL signal TRAFs (TNF receptor-associated factor protein) recruitment, transcription factor (NF-kB, AP-1, NFATc1), MAPK pathway (ERK, JNK, p38), Src Akt ( 2). 22
2 1. (Nat. Rev. Genet. 2003) OPG (osteoptotegerin) RANKL soluble decoy receptor RANKL signal. RANK/RANKL/OPG,.. 2. RANK signaling pathway (Nat. Rev. Genet. 2003),,,. 1.,,,,,. DNA microarray proteomic analysis. global DNA microarray. DNA microarray., TRAF bait yeast two hybrid system TRAF TIZ TRAF6 (2). TRAF6 new molecule affinity chromatography-ms(mass spec- 23
3 trometry) V-ATPase (vacuolar ATPase) TRAF6 (3). V-ATPase monocyte/macrophage lineage, H + pumping-out. V-ATPase TRAF6 RANKL stimulation, V-ATPase V- ATPase/TRAF6. Bone micro-environment (osteoclat), (octeoblast) (4, 3), communication. coupling-factor S1P (sphingosine-1-phosphate). SPHK (sphingosine kinase) sphingosine S1P, S1P secondary messenger, receptor primary messenger. SPHK S1P. S1P attenuation negative regulator, secretion S1P survival communication, (5). communication, (extracellular matrix) communication,. HA(hyaluronan). HA ECM component CD44. CD44 TLR4 (toll-like receptor 4) (6). HA TLR4 M-CSF signaling, ECM component innate immune receptor. 3. Bone microenvironment (Annu. Rev. Immunol. 2006) 2. Antigen-stimulated immune cell cytokine IL-1. immume system skeletal system (7, 4), 70., immune system skeletal system. Immune/skeletal system RA(rheumatoid arthritis) autoimmune disease. RA. collagen arthritis (CIA, collagen indiced arthritis) ( 5). hematopoietic stem cell. (osteoimmunology). Type I IFN (IFNα IFNβ) virus 24
4 5. CIA (Collagen-induced arthritis) 4. The osteoimmune system (Nature Rev. Immunol. 2007) pathogen host cytokine cytokine. proteomic-profiling study Jak1, JAK1 IFN-β (8)., Jak1 IFN-β, Jak1 poc (pre-osteoclast) IFN-β., pathologic, physiologic function biomedical,. 3. (bone metastasis). Breast cancer prostate cancer 70% bone metastasis, lung, colon, stomach, bladder, uterus, rectum, thyroid, kidney cancer 15~30% bone metastasis (9, 6) Bone metastasis 350,000 Bone metastasis. Bone metastasis (10). Breast cancer Bone metastasis 80% 5. Bone metastasis,, hypercalcemia, nerve-compression syndrome. breast cancer bone resorption osteolytic metastasis, prostate cancer bone formation osteoblastic metastasis, osteoblastic metastasis 6. Bone metastasis (Nat. Rev. Cancer 2002) 25
5 ..,., marrow stromal cell bone matrix adhesive molecule., immobilized growth factor (TGF-β, IGF I and II, FGF, PDGF, BMP, calcium). Breast cancer cell PTHrP secretion, PTHrP osteoblast RANKL. RANKL osteoclast precursor osteoclast osteoclast activity bone resorption. Bone resorption growth factor growth factor PTHrP secretion vicious cycle, Bone metastasis ( 7). Bone metastasis Bone metastasis. Bisphosphates bone remodeling rate, RANKL RANK OPG RANK-Fc, PTHrP neutralize PTHrP antibody, PTHrP production 7. Vicious cycle of bone metastasis (Nat. Rev. Cancer 2002) vitamin-d analogue., Bone metastasis., Bone metastasis ,390, 6, RANK/RAKL/OPG,., win-win. 1. Steven L. Teitelbaum and F. Patrick Ross. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, , Shin JN, Kim I, Lee JS, Koh GY, Lee ZH, Kim HH. A Novel Zinc Finger Protein that Inhibits Osteoclastogenesis and the Function of Tumor Necrosis Factor Receptor-Associated Factor 6. J. Biol. Chem. 277, , Ryu J, Kim H, Lee SK, Chang E, Kim HJ, Kim HH. Proteomic identification of the TRAF6 regulation of V-ATPase for osteoclast function. Proteomics. 5, , Walsh MC, Kim N, Kadono Y, Rho J, Lee SY, Lorenzo J, Cjoi Y. Osteoimmunology: interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 24, 33-63, Ryu J, Kim HJ, Chang E, Huang H, Banno Y, Kim 26
6 HH. Sphingosine 1-phosphate as a regulator for osteoclast differentiation and osteoclast-osteoblast coupling EMBO J. 25, , Chang E, Kim HJ, Ha H, Kim HJ, Ryu J, Park K, Kim U, Lee ZH, Kim H, Fisher DE, Kim HH. Hyaluronan inhibits osteoclast differentiation via Tolllike receptor 4. J. Cell Sci. 120, , Sci. STKE 2007, tw13 (2007). 7. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, , Lee Y, Hyung SW, Jung HJ, Kim HJ, Staerk J, Constantinescu SN, Chang EJ, Lee ZH, Lee SW, Kim HH. The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon- {beta}-induced inhibitory signaling. Blood Oct 10; [Epub ahead of print]. 9. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer. 2, , Roodman GD. Mechanisms of bone metastasis. N. Engl. J. Med. 350, ,
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