Receptor activator of nuclear factor кB ligand (RANKL) versus osteoprotegerin (OPG): the yin and yang of joint integrity

Rodan GA, Martin TJ (1981) Role of osteoblasts in hormonal control of bone resorption - a hypothesis. Calcif Tissue Int 33: 349–351PubMedGoogle Scholar

Jimi E, Nakamura I, Amano H, Taguchi Y, Tsurukai T, Tamura M, Takahashi N, Suda T (1996) Osteoclast function is activated by osteoblastic cells through a mechanism involving cell-to-cell contact. Endocrinology 137: 2187–2190Google Scholar

Katagiri T, Takahashi N (2002) Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Dis 8: 147–159PubMedGoogle Scholar

Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K (2002) Platelet-derived growth factor BB secreted from osteoclasts acts as an osteoblastogenesis inhibitory factor. J Bone MM Res 17: 257–265Google Scholar

Keyszer GM, Heer AH, Gay S (1994) Cytokines and oncogenes in cellular interactions of rheumatoid arthritis. Stem Cells 12: 75–86PubMedGoogle Scholar

Taubman MA, Kawai T (2001) Involvement of T-lymphocytes in periodontal disease and in direct and indirect induction of bone resorption. Crit Rev Oral Biol Med 12: 125–135PubMedGoogle Scholar

Lerner UH (1994) Regulation of bone metabolism by the kallikrein-kinin system, the coagulation cascade, and the acute-phase reactants. Oral Surg Oral Med Oral Pathol 78: 481–493PubMedGoogle Scholar

Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, Gillespie MT (1999) Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140: 4451–4458PubMedGoogle Scholar

Fuller K, Wong B, Fox S, Choi Y, Chambers TJ (1998) TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 188: 997–1001PubMedGoogle Scholar

Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: 165–176PubMedGoogle Scholar

Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A et al (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95: 3597–3602PubMedGoogle Scholar

Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289: 1504–1508PubMedGoogle Scholar

Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y (1997) TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 186: 2075–2080Google Scholar

HUGO Gene Nomenclature Committee (1998) The new TNF nomenclature scheme. http://www.gene.ucl.ac.uldnomenclature/genefamily/tnftop.html. (Last accessed March 18, 2003)Google Scholar

Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, E. C, Bartlett FSI, Frankel WN et al (1997) TRANCE is a novel ligand of the tumor necrosis receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 272: 25190–25194PubMedGoogle Scholar

Kodaira K, Mizuno A, Yasuda H, Shima N, Murakami A, Ueda M, Higashio K (1999) Cloning and characterization of the gene encoding mouse osteoclast differentiation factor. Gene 230: 121–127PubMedGoogle Scholar

Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T cell growth and dendritic cell function. Nature 390: 175–179PubMedGoogle Scholar

Kitazawa R, Kitazawa S (2002) Vitamin D₃ augments osteoclastogenesis via vitamin D-responsive element of mouse RANKL gene promoter. Biochem Biophys Res Comm 290: 650–655PubMedGoogle Scholar

Kitazawa S, Kitazawa R (2002) Epigenetic control of mouse receptor activator of NF-kB ligand gene expression. Biochem Biophys Res Comm 293: 126–131PubMedGoogle Scholar

Lam J, Nelson CA, Ross PF, Teitelbaum SL, Fremont DH (2001) Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. J Clin Invest 108: 971–979PubMedGoogle Scholar

Ito S, Wakabayashi K, Ubukata O, Hayashi S, Okada F, Hata T (2002) Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-Å resolution. J Biol Chem 277: 6631–6636PubMedGoogle Scholar

Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402: 304–309PubMedGoogle Scholar

Lum L, Wong BR, Josien R, Becherer JD, Erdjument-Bromage H, Schlondorff J, Tempst P, Choi Y, Blobel CP (1999) Evidence for a role of tumor necrosis factor-α (TNF-α)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem 274: 13613–13618PubMedGoogle Scholar

Ikeda T, Utsuyama M, Hirokawa K (2001) Expression profiles of receptor activator of nuclear factor kB ligand, receptor activator of nuclear factor kB, and osteoprotegerin messenger RNA in aged and ovariectomized rat bones. J Bone Min Res 16: 1416–1425Google Scholar

Nagai M, Sato N (1999) Reciprocal gene expression of osteoclastogenesis inhibitory factor and osteoclast differentiation factor regulates osteoclast formation. Biochem Biophys Res Comm 257: 719–723PubMedGoogle Scholar

Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M, Tak PP, Haynes DR (2002) Receptor activator of NF-kB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61: 1047–1054PubMedGoogle Scholar

Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S (2000) Involvement of receptor activator of nuclear factor kB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 43: 259–269PubMedGoogle Scholar

Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y, Kumegawa M, Kimura T, Takeya T (2002) Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 277: 41147–41156PubMedGoogle Scholar

Cappellen D, Luong-Nguyen N-H, Bongiovanni S, Grenet O, Wanke C, Susa M (2002) Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for the receptor activator of NF-kB. J Biol Chem 277: 21971–21982PubMedGoogle Scholar

Cyert MS (2001) Regulation of nuclear localization during signaling. J Biol Chem 276: 20805–20808PubMedGoogle Scholar

Macian F, Lopez-Rodriguez C, Rao A (2001) Partners in transcription: NFAT and AP1. Oncogene 20: 2476–2489PubMedGoogle Scholar

Gravallese EM, Galson DL, Goldring SR, Auron PE (2001) The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorption. Arthritis Res 3: 6–12PubMedGoogle Scholar

Itoh K, Udagawa N, Katagiri T, Iemura S, Ueno N, Yasuda H, Higashio K, Quinn JMW, Gillespie MT, Martin TJ et al (2001) Bone morphogenetic protein-2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kB ligand. Endocrinology 142: 3656–3662PubMedGoogle Scholar

Wani MR, Fuller K, Kim NS, Choi Y, Chambers TJ (1999) Prostaglandin E₂ cooperates with TRANCE in osteoclast induction from hemopoietic precursors: synergistic activation of differentiation, cell spreading, and fusion. Endocrinology 140: 1927–1935PubMedGoogle Scholar

Fuller K, Lean JM, Bayley KE, Wani MR, Chambers TJ (2000) A role for TGFβ1 in osteoclast differentiation and survival. J Cell Sci 113: 2445–2463PubMedGoogle Scholar

Fuller K, Bayley KE, Chambers TJ (2000) Activin A is an essential cofactor for osteoclast induction. Biochem Biophys Res Comm 268: 2–7PubMedGoogle Scholar

Murase Y, Okahashi N, Koseki T, Itoh K, Udagawa N, Hashimoto O, Sugino H, Noguchi T, Nishihara T (2001) Possible involvement of protein kinases and Smad2 signaling pathways on osteoclast differentiation enhanced by activin A. J Cell Physiol 188: 236–242PubMedGoogle Scholar

Iwamoto T, Fukumoto S, Kanaoka K, Sakai E, Shibata M, Fukumoto E, Inokuchi J-I, Takamiya K, Furukawa K, Furukawa K et al (2001) Lactosylceramide is essential for the osteoclastogenesis mediated by macrophage-colony stimulating factor and receptor activator of nuclear factor-kB ligand. J Biol Chem 276: 46031–46038PubMedGoogle Scholar

Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I et al (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96: 3540–3545PubMedGoogle Scholar

Kong YY, Boyle WJ, Penninger JM (2000) Osteoprotegerin ligand: a regulator of immune response and bone physiology. Immunol Today 21: 495–502PubMedGoogle Scholar

Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB (1998) Characterization of the intracellular domain of receptor activator of NF-kB (RANK) - interaction with tumor necrosis factor receptor-associated factors and activation of NF-kB and c-Jun N-terminal kinase. J Biol Chem 273: 20551–20555PubMedGoogle Scholar

Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC (1998) The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kB, a member of the TNFR superfamily. J Biol Chem 273: 34120–34127PubMedGoogle Scholar

Darnay BG, Ni J, Moore PA, Aggarwal BB (1999) Activation of NF-xB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kB -inducing kinase - Identification of a novel TRAF6 interaction motif. J Biol Chem 274: 7224–7731Google Scholar

Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M et al (1998) Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139: 1329–1337Google Scholar

Yun TJ, Chaudhary PM, Shu GL, Frazer JK, Ewings MK, Schwartz SM, Pascual V, Hood LE, Clark EA (1998) OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is upregulated by ligating CD40. J Immunol 161: 6113–6121PubMedGoogle Scholar

Kwon BS, Wang S, Udagawa N, Haridas V, Lee ZH, Kim KK, Oh KO, Greene J, Li Y, Su J et al (1998) TR1, a new member of the tumor necrosis factor receptor superfamily, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption. FASEB J 12: 845–854PubMedGoogle Scholar

Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K (1998) Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor. Eur J Biochem 254: 685–691PubMedGoogle Scholar

Thirunavukkarasu K, Halladay DL, Miles RR, Yang XH, Galvin RJS, Chandrasekhar S, Martin TJ, Onyia JE (2000) The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function. J Biol Chem 275: 25163–25172PubMedGoogle Scholar

Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luethy R, Nguyen HQ, Wooden S, Bennett L, Boone T et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: 309–319PubMedGoogle Scholar

Tomoyasu A, Goto M, Fujise N, Mochizuki S, Yasuda H, Morinaga T, Tsuda E, Higashio K (1998) Characterization of monomeric and homodimeric forms of osteoclastogenesis inhibitory factor. Biochem Biophys Res Comm 245: 382–387PubMedGoogle Scholar

Yano K, Shibata O, Mizuno A, Kobayashi F, Higashio K, Morinaga T, Tsuda E (2001) Immunological study on circulating murine osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF): possible role of OPG/OCIF in the prevention of osteoporosis in pregnancy. Biochem Biophys Res Comm 288: 217–224PubMedGoogle Scholar

Szulc P, Hofbauer LC, Heufelder AE, Roth S, Delmas PD (2001) Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J Clin Endocrinol Metab 86: 3162–3165PubMedGoogle Scholar

Khosla S, Arrighi HM, Melton LJI, Atkinson EJ, O’Fallon WM, Dunstan C, Riggs BL (2002) Correlates of osteoprotegerin levels in women and men. Osteoporosis Intl 13: 394–399Google Scholar

Fahrleitner A, Prenner G, Leb G, Tscheliessnigg KH, Piswanger-Solkner C, ObermayerPietsch B, Portugaller HR, Berghold A, Dobnig H (2003) Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation. Bone 32: 96–106PubMedGoogle Scholar

Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, Ikeda K, Higashio K, Yamada Y (1999) Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: Increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 14: 518–527PubMedGoogle Scholar

Yamaguchi K, Kinosaki M, Goto M, Kobayashi F, Tsuda E, Morinaga T, Higashio K (1998) Characterization of structural domains of human osteoclastogenesis inhibitory factor. J Biol Chem 273: 5117–5123PubMedGoogle Scholar

Standal T, Seidel C, Hjertner O Plesner T, Sanderson RD, Waage A, Borset M, Sundan A (2002) Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 100: 3002–3007PubMedGoogle Scholar

Nakamura H, Tsuji T, Hirata A, Yamamoto T (2002) Localization of osteoprotegerin (OPG) on bone surfaces and cement lines in rat tibia. J Histochem Cytochem 50: 945–953PubMedGoogle Scholar

Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, Valbracht J, CreightonAchermann L, Lotz M (2001) The osteoprotegerin/receptor activator of nuclear factor kB/receptor activator of nuclear factor ic13 ligand system in cartilage. Arthritis Rheum 44: 2768–2776PubMedGoogle Scholar

Emery JG, Mcdonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, Diprinzio R et al (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273: 14363–14367PubMedGoogle Scholar

Sedger LM, Glaccum MB, Schuh JCL, Kanaly ST, Williamson E, Kayagaki N, Yun T, Smolak P, Le T, Goodwin R et al (2002) Characterization of the in vivo function of TNF-α-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur J Immunol 32: 2246–2254PubMedGoogle Scholar

Zhou H, Kartsogiannis V, Hu YS, Elliott J, Quinn JMW, McKinstry WJ, Gillespie MT, Ng KW (2001) A novel osteoblast-derived C-type lectin that inhibits osteoclast formation. J Biol Chem 276: 14916–14923PubMedGoogle Scholar

Li J, Sarosi I, Yan X-Q, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G et al (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97: 1566–1571PubMedGoogle Scholar

Tsukii K, Shima N, Mochizuki S, Yamaguchi K, Kinosaki M, Yano K, Shibata O, Udagawa N, Yasuda H, Suda T et al (1998) Osteoclast differentiation factor mediates an essential signal for bone resorption induced by lα,25-dihydroxyvitamin D₃, prostaglandin E₂, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Comm 246: 337–341PubMedGoogle Scholar

Morony S, Capparelli C, Lee R, Shimamoto G, Boone T, Lacey DL, Dunstan CR (1999) A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1β, TNF-α, PTH, PTHrP, and 1,25(OH)₂D₃. J Bone Min Res 14: 1478–1485Google Scholar

Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15: 2–12PubMedGoogle Scholar

Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140: 4382–4389PubMedGoogle Scholar

Vidal NOA, Brändström H, Jonsson KB, Ohlsson C (1998) Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: downregulation by glucocorticoids. J Endocrinol 159: 191–195PubMedGoogle Scholar

Hofbauer LC, Shui C, Riggs BL, Dunstan CR, Spelsberg TC, O’Brien T, Khosla S (2001) Effects of immunosuppressants on receptor activator of NF-kB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Comm 280: 334–339PubMedGoogle Scholar

Chikazu D, Katagiri M, Ogasawara T, Ogata N, Shimoaka T, Takato T, Nakamura K, Kawaguchi H (2001) Regulation of osteoclast differentiation by fibroblast growth factor-2: stimulation of receptor activator of nuclear factor kB ligand/osteoclast differentiation factor expression in osteoblasts and inhibition of macrophage colony-stimulating factor function in osteoclast precursors. J Bone Min Res 16: 2074–2081Google Scholar

Rubin J, Ackert-Bicknell CL, Zhu L, Fan X, Murphy TC, Nanes MS, Marcus R, Holloway L, Beamer WG, Rosen CJ (2002) IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand in vitro and OPG in vivo. J Clin Endocrinol Metab 87: 4273–4279PubMedGoogle Scholar

Brändström H, Jonsson KB, Ohlsson C, Vidal O, Ljunghall S, Ljunggren Ö (1998) Regulation of osteoprotegerin mRNA levels by prostaglandin E₂ in human bone marrow stromal cells. Biochem Biophys Res Comm 247: 338–341PubMedGoogle Scholar

Murakami T, Yamamoto M, Ono K, Nishikawa M, Nagata N, Motoyoshi K, Akatsu T (1998) Transforming growth factor-β1 increases mRNA levels of osteoclastogenesis inhibitory factor in osteoblastic/stromal cells and inhibits the survival of murine osteoclast-like cells. Biochem Biophys Res Comm 252: 747–752PubMedGoogle Scholar

Brändström H, Bjorkman T, Ljunggren Ö (2001) Regulation of osteoprotegerin secretion from primary cultures of human bone marrow stromal cells. Biochem Biophys Res Comm 280: 831–835PubMedGoogle Scholar

Gruber R, Karreth F, Fischer MB, Watzek G (2002) Platelet-released supernatants stimulate formation of osteoclast-like cells through a prostaglandin/RANKL-dependent mechanism. Bone 30: 726–732PubMedGoogle Scholar

Horwood NJ, Elliott J, Martin TJ, Gillespie MT (1998) Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 139: 4743–4746PubMedGoogle Scholar

Lee SK, Lorenzo JA (1999) Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endorinology 140: 3552–3561Google Scholar

Itoh K, Udagawa N, Matsuzaki K, Takami M, Amano H, Shinki T, Ueno Y, Takahashi N, Suda T (2000) Importance of membrane-or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by Sa0S-4/3 cells expressing recombinant PTH/PTHrP receptors. J Bone Min Res 15: 1766–1775Google Scholar

Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin TJ, Onyia JE (2001) Catabolic effects of continuous human PTH (1–38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 142: 4047–4054PubMedGoogle Scholar

Miura M, Tanaka K, Komatsu Y, Suda M, Yasoda A, Sakuma Y, Ozasa A, Nakao K (2002) A novel interaction between thyroid hormones and 1,25(OH)₂D₃ in osteoclast formation. Biochem Biophys Res Comm 291: 987–994PubMedGoogle Scholar

Quinn JM, Horwood NJ, Elliott J, Gillespie MT, Martin TJ (2000) Fibroblastic stromal cells express receptor activator of NF-kB ligand and support osteoclast differentiation. J Bone Min Res 15: 1459–1466Google Scholar

Takai H, Kanematsu M, Yano K, Tsuda E, Higashio K, Ikeda K, Watanabe K, Yamada Y (1998) Transforming growth factor-β stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells. J Biol Chem 273: 27091–27096PubMedGoogle Scholar

Yamagishi T, Otsuka E, Hagiwara H (2001) Reciprocal control of expression of mRNAs for osteoclast differentiation factor and OPG in osteogenic stromal cells by genistein: evidence for the involvement of topoisomerase II in osteoclastogenesis. Endocrinology 142: 3632–3637PubMedGoogle Scholar

Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL (1999) Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140: 4367–4370PubMedGoogle Scholar

Lindberg MK, Erlandsson M, Alatalo SL, Windahl S, Andersson G, Halleen JM, Carlsten H, Gustafsson J-Å, Ohlsson C (2001) Estrogen receptor α, but not estrogen receptor β, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-kB ligand) ratio and serum interleukin-6 in male mice. J Endocrinol 171: 425–433PubMedGoogle Scholar

Srivasta S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R (2001) Estrogen decreases osteoclast formation by downregulating receptor activator of NF-kB ligand (RANKL)-induced JNK activation. J Biol Chem 276: 8836–8840Google Scholar

Shevde NK, Bendixen AC, Dienger KM, Pike JW (2000) Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 97: 7829–7834PubMedGoogle Scholar

Holloway WR, Collier FM, Aitken CJ, Myers DE, Hodge JM, Malakellis M, Gough T J., Collier GR, Nicholson GC (2002) Leptin inhibits osteoclast generation. J Bone Min Res 17: 200–209Google Scholar

Koyama H, Nakade O, Takada Y, Kaku T, Lau K-HW (2002) Melatonin at pharmacologic doses increases bone mass by suppressing resorption through downregulation of the RANKL-mediated osteoclast formation and activation. J Bone Min Res 17: 1219–1229Google Scholar

Hofbauer LC, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1998) Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines. Biochem Biophys Res Comm 250: 776–781PubMedGoogle Scholar

Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-1β and tumor necrosis factor-α, but not interleukin-1β, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25: 255–259PubMedGoogle Scholar

Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103: 1345–1352PubMedGoogle Scholar

Brandstrom H, Jonsson KB, Vidal O, Ljunghall S, Ohlsson C, Ljunggren O (1998) Tumor necrosis factor-α and -β upregulate the levels of osteoprotegerin mRNA in human osteosarcoma MG-63 cells. Biochem Biophys Res Comm 248: 454–457PubMedGoogle Scholar

Udagawa N, Takahashi N, Yasuda H, Mizuno A, Itoh K, Ueno Y, Shinki T, Gillespie MT, Martin TJ, Higashio K et al (2000) Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141: 3478–3484PubMedGoogle Scholar

Yamamoto M, Murakami T, Nishikawa M, Tsuda E, Mochizuki S, Higashio K, Akatsu T, Motoyoshi K, Nagata N (1998) Hypocalcemic effect of osteoclastogenesis inhibitory factor/osteoprotegerin in the thyroparathyroidectomized rat. Endocrinology 139: 4012–4015PubMedGoogle Scholar

Akatsu T, Murakami T, Ono K, Nishikawa M, Tsuda E, Mochizuki SI, Fujise N, Higashio K, Motoyoshi K, Yamamoto M et al (1998) Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. Bone 23: 495–498PubMedGoogle Scholar

Capparelli C, Kostenuik PJ, Morony S, Starnes C, Weimann B, Van G, Scully S, Qi MY, Lacey DL, Dunstan CR (2000) Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy. Cancer Res 60: 783–787PubMedGoogle Scholar

Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM (2001) Osteoprotegerin and receptor activator of nuclear factor kB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology 40: 623–630PubMedGoogle Scholar

Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wiland P, Dziewczopolski W, Filipowicz-Sosnowska A, Pazdur J, Szechinski J, Kowalczewski J et al (2002) High levels of osteoprotegerin and soluble receptor activator of nuclear factor kB ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor a treatment. Arthritis Rheum 46: 1744–1753PubMedGoogle Scholar

Arch RH, Gedrich RW, Thompson CB (1998) Tumor necrosis factor receptor-associated factors (TRAFs) - a family of adaptor proteins that regulate life and death. Genes Dev 12: 2821–2830PubMedGoogle Scholar

Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH, Ni JA, Kwon BS, Lee ZH (1999) Receptor activator of NF-kB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett 443: 297–302PubMedGoogle Scholar

Nguyen LT, Duncan GS, Mirtsos C, Ng M, Speiser DE, Shahinian A, Marino MW, Mak TW, Ohashi PS, Yeh WC (1999) TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and impairment of CD40-mediated responses. Immunity 11: 379–389PubMedGoogle Scholar

Kanazawa K, Azuma Y, Nakano H, Kudo A (2003) TRAFS functions in both RANKLand TNF α-induced osteoclastogenesis. J Bone Min Res 18: 443–450Google Scholar

Kaji K, Katogi R, Azuma Y, Naito A, Inoue JI, Kudo A (2001) Tumor necrosis factor α-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Min Res 16: 1593–1599Google Scholar

Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (1996) TRAF6 is a signal transducer for interleukin-1. Nature 383: 443–446PubMedGoogle Scholar

Armstrong AP, Tometsko ME, Glaccum M, Sutherland CL, Cosman D, Dougall WC (2002) A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem 277: 44347–44356PubMedGoogle Scholar

Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M et al (2002) Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418: 443–447PubMedGoogle Scholar

Schwandner R, Yamaguchi K, Cao ZD (2000) Requirement of tumor necrosis factor receptor-associated factor (TRAF) 6 in interleukin-17 signal transduction. J Exp Med 191: 1233–1239PubMedGoogle Scholar

Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J et al (2002) Induction and activation of the transcription factor NFATcl (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Develop Cell 3: 889–901Google Scholar

Wong BR, Besser D, Kim N, Arron JR, Vologodskaia M, Hanafusa H, Choi Y (1999) TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 4: 1041–1049PubMedGoogle Scholar

Lee SE, Chung WJ, Kwak HB, Chung CH, Kwack K, Lee ZH, Kim HH (2001) Tumor necrosis factor-α supports the survival of osteoclasts through the activation of Akt and ERK. J Biol Chem 276: 49343–49349PubMedGoogle Scholar

Lee SE, Woo KM, Kim SY, Kim H-M, Kwack K, Lee ZH, Kim H-H (2002) The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone 30: 70–77Google Scholar

Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Nishina H, Katada T, Wakabayashi K, Oda H, Nakamura K et al (2002) Possible involvement of IicB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kB ligand. J Bone Min Res 17: 612–621Google Scholar

Li X, Udagawa N, Itoh K, Suda K, Murase Y, Nishihara T, Suda T, Takahashi N (2002) p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology 143: 3105–3113PubMedGoogle Scholar

Karin M, Liu Z, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9: 240–246PubMedGoogle Scholar

Lee ZH, Kwack K, Kim KK, Lee SH, Kim HH (2000) Activation of c-Jun N-terminal kinase and activator protein-1 by receptor activator of nuclear factor kB. Mol Pharmacol 58: 1536–1545PubMedGoogle Scholar

Zhou B, Cron RQ, Wu BR, Genin A, Wang ZL, Liu S, Robson P, Baldwin HS (2002) Regulation of the murine Nfatc1 gene by NFATc2. J Biol Chem 277: 10704–10711PubMedGoogle Scholar

Battaglino R, Kim D, Fu J, Vaage B, Fu X-Y, Stashenko P (2002) c-myc is required for osteoclast differentiation. J Bone Min Res 17: 763–773Google Scholar

Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F, Boyce BF (2002) NF-kB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis. J Bone Min Res 17: 1200–1210Google Scholar

Hayashi T, Kaneda T, Toyama Y, Kumegawa M, Hakeda Y (2002) Regulation of receptor activator of NF-kB ligand-induced osteoclastogenesis by endogenous interferon-β (INF-β) and suppressors of cytokine signaling (SOCS). The possible counteracting role of SOCSs in IFN-β-inhibited osteoclast formation. J Biol Chem 277: 27880–27886PubMedGoogle Scholar

Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N et al (2002) RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β. Nature 416: 744–749PubMedGoogle Scholar

Shin JN, Kim I, Lee JS, Koh GY, Lee ZH, Kim HH (2002) A novel zinc finger protein that inhibits osteoclastogenesis and the function of tumor necrosis factor receptor-associated factor 6. J Biol Chem 277: 8346–8353PubMedGoogle Scholar

Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K et al (2000) T cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408: 600–605PubMedGoogle Scholar

Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y (2001) Tumor necrosis factor-α (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem 276: 563–568PubMedGoogle Scholar

Lean JM, Matsuo K, Fox SW, Fuller K, Gibson FM, Draycott G, Wani MR, Bayley KE, Wong BR, Choi Y et al (2000) Osteoclast lineage commitment of bone marrow precursors through expression of membrane-bound TRANCE. Bone 27: 29–40PubMedGoogle Scholar

Shalhoub V, Faust J, Boyle WJ, Dunstan CR, Kelley M, Kaufman S, Scully S, Van G, Lacey DL (1999) Osteoprotegerin and osteoprotegerin ligand effects on osteoclast formation from human peripheral blood mononuclear cell precursors. J Cell Biochem 72: 251–261PubMedGoogle Scholar

Campagnuolo G, Bolon B, Feige U (2002) Kinetics of bone protection by recombinant osteoprotegerin therapy in Lewis rats with adjuvant arthritis. Arthritis Rheum 46: 1926–1936PubMedGoogle Scholar

Romas E, Sims NA, Hards D, Lindsay M, Quinn JWM, Ryan PFJ, Dunstan CR, Martin TJ, Gillespie MT (2002) Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 161: 1419–1427PubMedGoogle Scholar

Jimi E, Akiyama S, Tsurukai T, Okahashi N, Kobayashi K, Udagawa NT.N, Takahashi N, Suda T (1999) Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol 163: 434–442PubMedGoogle Scholar

Hakeda Y, Kobayashi Y, Yamaguchi K, Yasuda H, Tsuda E, Higashio K, Miyata T, Kumegawa M (1998) Osteoclastogenesis inhibitory factor (OCIF) directly inhibits boneresorbing activity of isolated mature osteoclasts. Biochem Biophys Res Comm 251: 796–801PubMedGoogle Scholar

O’Brien EA, Williams JHH, Marshall MJ (2000) Osteoprotegerin ligand regulates osteoclast adherence to the bone surface in mouse calvaria. Biochem Biophys Res Comm 274: 281–290PubMedGoogle Scholar

O’Brien EA, Williams JHH, Marshall MJ (2001) Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach to the endocranial membrane. Bone 28: 208–214PubMedGoogle Scholar

Wittrant Y, Couillaud S, Theoleyre S, Dunstan C, Heymann D, Redini F (2002) Osteoprotegerin differentially regulates protease expression in osteoclast cultures. Biochem Biophys Res Comm 293: 38–44PubMedGoogle Scholar

Akatsu T, Murakami T, Nishikawa M, Ono K, Shinomiya N, Tsuda E, Mochizuki S, Yamaguchi K, Kinosaki M, Higashio K et al (1998) Osteoclastogenesis inhibitory factor suppresses osteoclast survival by interfering in the interaction of stromal cells with osteoclasts. Biochem Biophys Res Comm 250: 229–234PubMedGoogle Scholar

Lacey DL, Tan HL, Lu J, Kaufman S, Van G, Qiu WR, Rattan A, Scully S, Fletcher F, Juan T et al (2000) Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 157: 435–448PubMedGoogle Scholar

Bolon B, Campagnuolo G, Feige U (2002) Duration of bone protection afforded by a single injection of recombinant osteoprotegerin (OPG) in male Lewis rats with adjuvant arthritis. Cell Mol Life Sci 59: 1569–1576PubMedGoogle Scholar

Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira dos Santos AJ, Van G, Itie A et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis. Nature 397: 315–323PubMedGoogle Scholar

Kim N, Odgren PR, Kim DK, Marks SCJ, Choi Y (2000) Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci USA 97: 10905–10910PubMedGoogle Scholar

Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL et al (2000) Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 192: 463–474PubMedGoogle Scholar

Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL et al (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12: 1260–1268PubMedGoogle Scholar

Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13: 1015–1024PubMedGoogle Scholar

Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T et al (1999) Severe osteopetrosis, defective interleukin-1 signaling and lymph node organogenesis in TRAF6-deficient mice. Genes to Cells 4: 353–362PubMedGoogle Scholar

Boyce BF, Hughes DE, Wright KR, Xing LP, Dai AH (1999) Recent advances in bone biology provide insight into the pathogenesis of bone diseases. Lab Invest 79: 83–94PubMedGoogle Scholar

Wang ZQ, Ovitt C, Grigoriadis A, Mohle-Ateinlein U, Ruther U, Wagner EF (1992) Bone and haematopoeitic defects in mice lacking c-fos. Nature 360: 741–745PubMedGoogle Scholar

Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U (1997) Requirement for NF-idi in osteoclast and B-cell development. Genes Dev 11: 3482–3496PubMedGoogle Scholar

Matsuo K, Owens JM, Tonko M, Elliot C, Chambers TJ, Wagner EF (2000) Fos11 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet 24: 184–187PubMedGoogle Scholar

Janssens K, Van Hul W (2002) Molecular genetics of too much bone. Hum Mol Genet 11: 2385–2393PubMedGoogle Scholar

Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RGH, van Hul W, Whyte MP, Nakatsuka K, Hovy L et al (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24: 45–48PubMedGoogle Scholar

Whyte MP, Hughes AE (2002) Expansile skeletal hyperphosphatasia is caused by a 15- base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Min Res 17: 26–29Google Scholar

Laurin N, Brown JP, Morissette J, Raymond V (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70: 1582–1588PubMedGoogle Scholar

Sanz L, Sanchez P, Lallena MJ, Diaz M, Moscat J (1999) The interaction of p62 with RIP links the atypical PKCs to NF-kB activation. EMBO J 18: 3044–3053PubMedGoogle Scholar

Sparks AB, Peterson SN, Bell C, Loftus BJ, Hocking L, Cahill DP, Frassica FJ, Streeten EA, Levine MA, Fraser CM et al (2001) Mutation screening of the TNFRSF11A gene encoding receptor activator of NFKB (RANK) in familial and sporadic Paget’s disease of bone and osteosarcoma. Cakif Tissue Int 68: 151–155Google Scholar

Wuyts W, van Wesenbeeck L, Morales-Piga A, Ralston S, Hocking L, Vanhoenacker F, Westhovens R, Verbruggen L, Anderson D, Hughes A et al (2001) Evaluation of the role of RANK and OPG genes in Paget’s disease of bone. Bone 28: 104–107PubMedGoogle Scholar

Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, Love DR, Seidel J, Fawkner M, Banovic T et al (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11: 2119–2127PubMedGoogle Scholar

Shimizu S, Shiozawa S, Shiozawa K, Imura S, Fujita T (1985) Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis. Arthritis Rheum 28: 25–31PubMedGoogle Scholar

Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR (1998) Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 152: 943–951PubMedGoogle Scholar

Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR (2000) Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43: 250–258PubMedGoogle Scholar

Toraldo G, Roggia C, Qian WP, Pacifici R, Weitzmann MN (2003) IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kB and tumor necrosis factor-α from T cells. Proc Natl Acad Sci USA 100: 125–130PubMedGoogle Scholar

Romas E, Bakharevski O, Hards DK, Kartsogiannis V, Quinn JM, Ryan PF, Martin TJ, Gillespie MT (2000) Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum 43: 821–826PubMedGoogle Scholar

Lubberts E, Oppers-Walgreen B, Pettit AR, van den Bersselaar L, Joosten LAB, Goldring SR, Gravallese EM, van den Berg WB (2002) Increase in expression of receptor activator of nuclear factor kB at sites of bone erosion correlates with progression of inflammation in evolving collagen-induced arthritis. Arthritis Rheum 46: 3055–3064PubMedGoogle Scholar

Mori H, Kitazawa R, Mizuki S, Nose M, Maeda S, Kitazawa S (2002) RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse. Histochem Cell Biol 117: 283–292PubMedGoogle Scholar

Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takahashi K, Furuya T, Ishiyama S, Kim K-J et al (2001) Activated human T cells directly induce osteoclastogenesis from human monocytes. Arthritis Rheum 44: 1003–1012PubMedGoogle Scholar

Choi Y, Woo KM, Ko S-H, Lee YJ, Park S-J, Kim H-M, Kwon BS (2001) Osteoclasto-genesis is enhanced by activated B cells but suppressed by activated CD8₊ T cells. Eur J Immunol 31: 2179–2188Google Scholar

Manabe N, Kawaguchi H, Chikuda H, Miyaura C, Inada M, Nagai R, Nabeshima Y, Nakamura K, Sinclair A, Scheuermann RH et al (2001) Connection between B lymphocyte and osteoclast differentiation pathways. J Immunol 167: 2625–2631PubMedGoogle Scholar

Tsurukai T, Udagawa N, Matsuzaki K, Takahashi N, Suda T (2000) Roles of macrophage-colony stimulating factor and osteoclast differentiation factor in osteoclastogenesis. J Bone Min Res 18: 177–184Google Scholar

Feuerherm AJ, Borset M, Seidel C, Sundan A, Leistad L, Ostensen M, Faxvaag A (2001) Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. Scand J Rheumatol 30: 229–234PubMedGoogle Scholar

Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, Benoist C, Gravallese EM (2001) TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 159: 1689–1699PubMedGoogle Scholar

Toritsuka Y, Nakamura N, Lee SB, Hashimoto J, Yasui N, Shino K, Ochi T (1997) Osteoclastogenesis in iliac bone marrow of patients with rheumatoid arthritis. J Rheumatol 24: 1690–1696PubMedGoogle Scholar

Romas E, Gillespie MT, Martin TJ (2002) Involvement of receptor activator of NFβ ligand and tumor necrosis factor-α in bone destruction in rheumatoid arthritis. Bone 30: 340–346PubMedGoogle Scholar

Gough A, Sambrook P, Devlin J, Huisson A, Njeh C, Robbins P et al (1998) Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 25: 1282–1289PubMedGoogle Scholar

Hirayama T, Danks L, Sabokbar A, Athanasou NA (2002) Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology 41: 1232–1239PubMedGoogle Scholar

Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13: 2412–2424PubMedGoogle Scholar

Matsumoto M, al. e (1996) Role of lymphotoxin and the type I TNF receptor in the formation of germinal centers. Science 271: 1289–1291PubMedGoogle Scholar

Josien R, Wong BR, Li HL, Steinman RM, Choi Y (1999) TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol 162: 2562–2568PubMedGoogle Scholar

Yamashita T, Okada S, Higashio K, Nabeshima Noda M (2002) Double mutations in klotho and osteoprotegerin gene loci rescued osteopetrotic phenotype. Endocrinology 143: 4711–4717PubMedGoogle Scholar

Yun TJ, Tallquist MD, Aicher A, Rafferty KL, Marshall AJ, Moon JJ, Ewings MK, Mohaupt M, Herring SW, Clark EA (2001) Osteoprotegerin, a crucial regulator of bone metabolism, also regulates B cell development and function. J Immunol 166: 1482–1491PubMedGoogle Scholar

Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392: 245–252PubMedGoogle Scholar

Josien R, Li HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M, Steinman RM, Choi Y (2000) TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 191: 495–502Google Scholar

Williamson E, Bilsborough JM, Viney JL (2002) Regulation of mucosal dendritic cell function by receptor activator of NF-kB (RANK)/RANK ligand interactions: impact on tolerance induction. J Immunol 169: 3606–3612PubMedGoogle Scholar

Ueland T, Bollerslev J, Godang K, Muller F, Froland SS, Aukrust P (2001) Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess: possible role in bone homeostasis. Eur J Endocrinol 145: 685–690PubMedGoogle Scholar

Martin TJ, Gillespie MT (2001) Receptor activator of nuclear factor ^-kB ligand (RANKL): another link between breast and bone. Tr Endocrinol Metab 12: 2–4Google Scholar

Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL et al (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103: 41–50PubMedGoogle Scholar

Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM (2000) Osteoprotegerin is an α_vβ₃-induced, NF-kB -dependent survival factor for endothelial cells. J Biol Chem 275: 20959–20962PubMedGoogle Scholar

Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, Chen YE (2002) PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett 521: 180–184PubMedGoogle Scholar

Fu MG, Zhang JF, Lin YM, Zhu XJ, Willson TM, Chen YQE (2002) Activation of peroxisome proliferator-activated receptor y inhibits osteoprotegerin gene expression in human aortic smooth muscle cefls. Biochem Biophys Res Comm 294: 597–601PubMedGoogle Scholar

Price PA, June HH, Buckley JR, Williamson MK (2001) Osteoprotegerin inhibits artery calcification induced by warfarin and vitamin D. Arterioscler Thromb Vasc Biol 21: 1610–1616PubMedGoogle Scholar

Parhami F, Demer LL (1997) Arterial calcification in face of osteoporosis in aging: can we blame oxidized lipids? Curr Opin Lipidol 8: 312–314PubMedGoogle Scholar

Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC (2000) Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol 20: 1926–1931PubMedGoogle Scholar

Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, Nishizawa Y (2002) Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 106: 1192–1194PubMedGoogle Scholar

Dhore CR, Cleutjens JPM, Lutgens E, Cleutjens KBJM, Geusens PPM, Kitslaar PJEHM, Tordoir JHM, Spronk HMH, Vermeer C, Daemen MJAP (2001) Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioclero Thromb Vasc Biol 21: 1998–2003Google Scholar

Brändström H, Stiger F, Lind L, Kahan T, Melhus H, Kindmark A (2002) A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function. Biochem Biophys Res Comm 293: 13–17PubMedGoogle Scholar

Wong M, Toh L, Wilson A, Rowley K, Karschimkus C, Prior D, Romas E, Clemens L, Dragicevic G, Harianto H et al (2003) Reduced arterial elasticity in rheumatoid arthritis and the relationship to vascular disease risk factors and inflammation. Arthritis Rheum 48: 81–89PubMedGoogle Scholar

Martin SW, Sommers JS, Watson AM, Young JD, Dunstan CR (1999) The pharmacokinetics and pharmacodynamics of OPG following single dose administration in cynomolgus monkeys. J Bone Miner Res 14 (Suppl 1): S399Google Scholar

Feldmann M, Brennan FM, Maini RN (1996) Rheumatoid arthritis. Cell 85: 307–310PubMedGoogle Scholar

Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N et al (2000) Tumor necrosis factor a stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191: 275–286PubMedGoogle Scholar

Suda T, Kobayashi K, Jimi E, Udagawa N, Takahashi N (2001) The molecular basis of osteoclast differentiation and activation. Novartis Found Symp 232: 235–247 (discussion 247–250)PubMedGoogle Scholar

Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT (1999) Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Comm 265: 144–150Google Scholar

Xu LX, Kukita T, Nakano Y, Yu H, Hotokebuchi T, Kuratani T, lijima T, Koga T (1996) Osteoclasts in normal and adjuvant arthritis bone tissues express the mRNA for both type I and II interleukin-1 receptors. Lab Invest 75: 677–687PubMedGoogle Scholar

Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P (2001) Receptor activator of NF-kB and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 276: 20659–20672PubMedGoogle Scholar

Feige U, Hu Y-L, Gasser J, Campagnuolo G, Munyakazi L, Bolon B (2000) Anti-interleukin-1 and anti-tumor necrosis factor-αsynergistically inhibit adjuvant arthritis in Lewis rats. Cell Mol Life Sci 57: 1457–1470PubMedGoogle Scholar

Kimble RB, Srivastava S, Ross FP, Matayoshi A, Pacifici R (1996) Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1 and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production. J Biol Chem 271: 28890–28897PubMedGoogle Scholar

Fox SW, Fuller K, Chambers TJ (2000) Activation of osteoclasts by interleukin-1: divergent responsiveness in osteoclasts formed in vivo and in vitro. J Cell Physiol 184: 334–340Google Scholar

Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ (2002) TNF-α potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology 143: 1108–1118PubMedGoogle Scholar

Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA (2002) Proinflammatory cytokine (TNFα/IL-1α) induction of human osteoclast formation. J Pathol 198: 220–227PubMedGoogle Scholar

Zou W, Hakim I, Tschoep K, Endres S, Bar-Shavit Z (2001) Tumor necrosis factor-α mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism. J Cell Biochem 83: 70–83PubMedGoogle Scholar

Lam J, Takeshita S, Barker JE, Kanagawa 0, Ross F, Teitelbaum SL (2000) TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 106: 1481–1488PubMedGoogle Scholar

Bekker PJ, Holloway D, Nakanishi A, Arrighi HM, Leese PT, Dunstan CR (2001) The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16: 348–360PubMedGoogle Scholar

Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, Harousseau JL, Lipton A, Mariette X, Williams CD et al (2003) A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 97 (3 Suppl S): 887–892PubMedGoogle Scholar

Redlich K, Hayer S, Maier A, Dunstan CR, Tohidast-Akrad M, Lang S, Turk B, Pietschmann P, Woloszczuk W, Haralambous S et al (2002) Tümor necrosis factor ocmediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum 46: 785–792PubMedGoogle Scholar

Deyama Y, Kikuiri T, Ohnishi G-I, Feng Y-G, Takeyama S, Hatta M, Yoshimura Y, Suzuki K (2002) Histamine stimulates production of osteoclast differentiation factor/receptor activator of nuclear factor-kB ligand by osteoblasts. Biochem Biophys Res Comm 298: 240–246PubMedGoogle Scholar

O’Brien CA, Gubrij I, Lin SC, Saylors RL, Manolagas SC (1999) STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-kB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin1 but not 1,25-dihydroxyvitamin D₃ or parathyroid hormone. J Biol Chem 274: 19301–19308PubMedGoogle Scholar

Weitzmann MN, Cenci S, Rifas L, Brown C, Pacifici R (2000) Interleukin-7 stimulates osteoclast formation by upregulating the T cell production of soluble osteoclastogenic cytokines. Blood 96: 1873–1878PubMedGoogle Scholar

Makiishi-Shimobayashi C, Tsujimura T, Iwasaki T, Yamada N, Sugihara A, Okamura H, Hayashi S, Terada N (2001) Interleukin-18 upregulates osteoprotegerin expression in stromal/osteoblastic cells. Biochem Biophys Res Comm 281: 361–366PubMedGoogle Scholar

Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, Mizuno A, Higashio K, Takahashi N, Suda T et al (2001) Transforming growth factor-β affects osteoclast differentiation via direct and indirect actions. J Bone MM Res 16: 1787–1794Google Scholar

Thirunavukkarasu K, Miles RR, Halladay DL, Yang X, Galvin RJS, Chandrasekhar S, Martin TJ, Onyia JE (2001) Stimulation of osteoprotegerin (OPG) gene expression by transforming growth fact-β (TGF-β). J Biol Chem 276: 36241–36250PubMedGoogle Scholar

Hofbauer LC, Hicok KC, Chen D, Khosla S (2002) Regulation of osteoprotegerin production by androgens and anti-androgens in human osteoblastic lineage cells. Eur J Endocrinol 147: 269–273PubMedGoogle Scholar

Thomas GP, Baker SUK, Eisman JA, Gardiner EM (2001) Changing RANKL/OPG mRNA expression in differentiating murine primary osteoblasts. J Endocrinol 170: 451–460PubMedGoogle Scholar

Viereck V, Emons G, Lauck V, Frosch K-H, Blaschke S, Griindker C, Hofbauer LC (2002) Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Comm 291: 680–686PubMedGoogle Scholar

Takami M, Takahashi N, Udagawa N, Miyaura C, Suda K, Woo J, Martin T, Nagai K, Suda T (2000) Intracellular calcium and protein kinase C mediate expression of receptor activator of nuclear factor-kB ligand and osteoprotegerin in osteoblasts. Endocrinology 141: 4711–4719PubMedGoogle Scholar

Walton KJ, Duncan JM, Deschamps P, Shaughnessy SG (2002) Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation. Blood 100: 2530–2536PubMedGoogle Scholar

Yang X, Halladay D, Onyia JE, Martin TJ, Chandrasekhar S (2002) Protein kinase C is a mediator of the synthesis and secretion of osteoprotegerin in osteoblast-like cells. Biochem Biophys Res Comm 290: 42–46PubMedGoogle Scholar

Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz L, Nishikawa S (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345: 442–444PubMedGoogle Scholar

Okada S, Wang ZQ, Grigoriadis AE, Wagner EF, Vonruden T (1994) Mice lacking c-Fos have normal hematopoietic stem cells but exhibit altered B cell differentiation due to an impaired bone marrow environment. Mol Cell Biol 14: 382–390PubMedGoogle Scholar

Takeshita S, Namba N, Zhao JJ, Jiang Y, Genant HK, Silva MJ, Brodt MD, Helgason CD, Kalesnikoff J, Rauh MJ et al (2002) SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nature Med 8: 943–949PubMedGoogle Scholar

Kostenuik PJ, Capparelli C, Morony S, Adamu S, Shimamoto G, Shen V, Lacey DL, Dunstan CR (2001) OPG and PTH (1–34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology 142: 4295–4304PubMedGoogle Scholar

Bolon B, Carter C, Daris M, Morony S, Capparelli C, Hsieh A, Mao M, Kostenuik P, Dunstan CR, Lacey DL et al (2001) Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis. Mol Ther 3: 197–205PubMedGoogle Scholar