Abstract
Osteoporosis or rheumatoid arthritis are bone diseases affecting hundreds of millions of people worldwide and thus pose a tremendous burden to health care. Ground-breaking discoveries made in basic science over the last decade shed light on the molecular mechanisms of bone metabolism and bone turnover. Thereby, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three molecules, the receptor activator of NF-κB (RANK), its ligand RANKL and the decoy receptor of RANKL, osteoprotegerin (OPG), have been a major focus of scientists and pharmaceutical companies alike, since experiments using mice in which these genes have been inactivated unanimously established their pivotal role as central regulators of osteoclast function. RANK(L) signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various bone diseases, such as cancer metastases, osteoporosis, or arthropathies.
Access provided by Autonomous University of Puebla. Download to read the full chapter text
Chapter PDF
Similar content being viewed by others
Keywords
- Osteoclast Differentiation
- Osteoclast Development
- Osteoclast Differentiation Factor
- Familial Expansile Osteolysis
- Idiopathic Hyperphosphatasia
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 2(4):389–406.
Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T-cells, bone loss and mammalian evolution. Annu Rev Immunol 2002; 20:795–823.
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423(6937):337–342.
Wada T, Nakashima T, Hiroshi N et al. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 2006; 12(1):17–25.
Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med 2004; 351(27):2839–2849.
Anderson DM, Maraskovsky E, Billingsley WL et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997; 390(6656):175–179.
Wong BR, Rho J, Arron J et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T-cells. J Biol Chem 1997; 272(40):25190–25194.
Lacey DL, Timms E, Tan HL et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93(2):165–176.
Yasuda H, Shima N, Nakagawa N et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998; 95(7):3597–3602.
Yasuda H, Shima N, Nakagawa N et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 1998; 139(3):1329–1337.
Tsuda E, Goto M, Mochizuki S et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 1997; 234(1):137–142.
Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997; 89(2):309–319.
Dougall WC, Glaccum M, Charrier K et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13(18):2412–2424.
Kong YY, Yoshida H, Sarosi I et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397(6717):315–323.
Li J, Sarosi I, Yan XQ et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 2000; 97(4):1566–1571.
Lam J, Nelson CA, Ross FP et al. Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. J Clin Invest 2001; 108(7):971–979.
Ito S, Wakabayashi K, Ubukata O et al. Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution. J Biol Chem 2002; 277(8):6631–6636.
Wong BR, Josien R, Lee SY et al. 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 1997; 186(12):2075–2080.
Kartsogiannis V, Zhou H, Horwood NJ et al. Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone 1999; 25(5):525–534.
Fata JE, Kong YY, Li J et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000; 103(1):41–50.
Loser K, Mehling A, Loeser S et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 2006; 12(12):1372–1379.
Ikeda T, Kasai M, Utsuyama M et al. Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology 2001; 142(4):1419–1426.
Ikeda T, Kasai M, Suzuki J et al. Multimerization of the receptor activator of nuclear factor-kappaB ligand (RANKL) isoforms and regulation of osteoclastogenesis. J Biol Chem 2003; 278(47):47217–47222.
Suzuki J, Ikeda T, Kuroyama H et al. Regulation of osteoclastogenesis by three human RANKL isoforms expressed in NIH3T3 cells. Biochem Biophys Res Commun 2004; 314(4):1021–1027.
Schlondorff J, Lum L, Blobel CP. Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. J Biol Chem 2001; 276(18):14665–14674.
Chesneau V, Becherer JD, Zheng Y et al. Catalytic properties of ADAM19. J Biol Chem 2003; 278(25):22331–22340.
Lynch CC, Hikosaka A, Acuff HB et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 2005; 7(5):485–496.
Hikita A, Yana I, Wakeyama H et al. Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand. J Biol Chem 2006; 281(48):36846–36855.
Chan FK, Chun HJ, Zheng L et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 2000; 288(5475):2351–2354.
Siegel RM, Frederiksen JK, Zacharias DA et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 2000; 288(5475):2354–2357.
Chan KF, Siegel MR, Lenardo JM. Signaling by the TNF receptor superfamily and T-cell homeostasis. Immunity 2000; 13(4):419–422.
Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104(4):487–501.
Nakagawa N, Kinosaki M, Yamaguchi K et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 1998; 253(2):395–400.
Williamson E, Bilsborough JM, Viney JL. Regulation of mucosal dendritic cell function by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction. J Immunol 2002; 169(7):3606–3612.
Josien R, Wong BR, Li HL et al. TRANCE, a TNF family member, is differentially expressed on T-cell subsets and induces cytokine production in dendritic cells. J Immunol 1999; 162(5):2562–2568.
Gonzalez-Suarez E, Branstetter D, Armstrong A et al. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol Cell Biol 2007; 27(4):1442–1454.
Tan KB, Harrop J, Reddy M et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and nonhematopoietic cells. Gene 1997; 204(1–2):35–46.
Kwon BS, Wang S, Udagawa N et al. TR1, a new member of the tumor necrosis factor receptor superfamily, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption. FASEB J 1998; 12(10):845–854.
Bucay N, Sarosi I, Dunstan CR et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12(9):1260–1268.
Mizuno A, Amizuka N, Irie K et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 1998; 247(3):610–615.
Hsu H, Lacey DL, Dunstan CR et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999; 96(7):3540–3545.
Hughes AE, Ralston SH, Marken J et al. Mutations in TNFRSE11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 2000; 24(1):45–48.
Whyte MP, Mills BG, Reinus WR et al. Expansile skeletal hyperphosphatasia: A new familial metabolic bone disease. J Bone Miner Res 2000; 15(12):2330–2344.
Whyte MP, Hughes AE. 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 Miner Res 2002; 17(1):26–29.
Sobacchi C, Frattini A, Guerrini MM et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 2007; 39(8):960–962.
Cundy T, Hegde M, Naot D et al. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 2002; 11(18):2119–2127.
Chong B, Hegde M, Fawkner M et al. Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J Bone Miner Res 2003; 18(12):2095–2104.
Inoue J, Ishida T, Tsukamoto N et al. Tumor necrosis factor receptor-associated factor (TRAF) family: Adapter proteins that mediate cytokine signaling. Exp Cell Res 2000; 254(1):14–24.
Darnay BG, Haridas V, Ni J et al. Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J Biol Chem 1998; 273(32):20551–20555.
Wong BR, Josien R, Lee SY et al. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem 1998; 273(43):28355–28359.
Wong BR, Josien R, Choi Y. TRANCE is a TNF family member that regulates dendritic cell and osteoclast function. J Leukoc Biol 1999; 65(6):715–724.
Galibert L, Tometsko ME, Anderson DM et al. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 1998; 273(51):34120–34127.
Lee ZH, Kwack K, Kim KK et al. Activation of c-Jun N-terminal kinase and activator protein 1 by receptor activator of nuclear factor kappaB. Mol Pharmacol 2000; 58(6):1536–1545.
Lomaga MA, Yeh WC, Sarosi I et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40 and LPS signaling. Genes Dev 1999; 13(8):1015–1024.
Naito A, Azuma S, Tanaka S et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 1999; 4(6):353–362.
Kobayashi N, Kadono Y, Naito A et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 2001; 20(6):1271–1280.
Kobayashi T, Walsh PT, Walsh MC et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 2003; 19(3):353–363.
Ye H, Arron JR, Lamothe B et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 2002; 418(6896):443–447.
Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4(8):638–649.
Kanazawa K, Kudo A. TRAF2 is essential for TNF-alpha-induced osteoclastogenesis. J Bone Miner Res 2005; 20(5):840–847.
Kanazawa K, Azuma Y, Nakano H et al. TRAF5 functions in both RANKL-and TNFalpha-induced osteoclastogenesis. J Bone Miner Res 2003; 18(3):443–450.
Wada T, Nakashima T, Oliveira-dos-Santos AJ et al. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med 2005; 11(4):394–399.
Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3(3):221–227.
Iotsova V, Caamano J, Loy J et al. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 1997; 3(11):1285–1289.
Franzoso G, Carlson L, Xing L et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 1997; 11(24):3482–3496.
Ruocco MG, Maeda S, Park JM et al. I{kappa}B kinase (IKK)ta, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med 2005; 201(10):1677–1687.
Novack DV, Yin L, Hagen-Stapleton A et al. The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med 2003; 198(5):771–781.
Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 2004; 23(16):2838–2849.
Matsumoto M, Sudo T, Saito T et al. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem 2000; 275(40):31155–31161.
David JP, Sabapathy K, Hoffmann O et al. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and independent mechanisms. J Cell Sci 2002; 115(Pt 22):4317–4325.
Wagner EF. Functions of AP1 (Fos/Jun) in bone development. Ann Rheum Dis 2002; 61(Suppl 2): ii40–42.
Yamamoto A, Miyazaki T, Kadono Y et al. Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. J Bone Miner Res 2002; 17(4):612–621.
Kenner L, Hoebertz A, Beil T et al. Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol 2004; 164(4):613–623.
Hotokezaka H, Sakai E, Kanaoka K et al. U0126 and PD98059, specific inhibitors of MEK, accelerate differentiation of RAW264.7 cells into osteoclast-like cells. J Biol Chem 2002; 277(49):47366–47372.
Takayanagi H, Kim S, Koga T et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 2002; 3(6):889–901.
Takayanagi H. Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 2007; 7(4):292–304.
Asagiri M, Sato K, Usami T et al. autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 2005; 202(9):1261–1269.
Soriano P, Montgomery C, Geske R et al. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 1991; 64(4):693–702.
Wong BR, Besser D, Kim N et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 1999; 4(6):1041–1049.
Nakamura I, Takahashi N, Sasaki T et al. Wortmannin, a specific inhibitor of phosphatidylinositol-3 kinase, blocks osteoclastic bone resorption. FEBS Lett 1995; 361(1):79–84.
Kalesnikoff J, Sly LM, Hughes MR et al. The role of SHIP in cytokine-induced signaling. Rev Physiol Biochem Pharmacol 2003; 149:87–103.
Sugatani T, Alvarez U, Hruska KA. PTEN regulates RANKL-and osteopontin-stimulated signal transduction during osteoclast differentiation and cell motility. J Biol Chem 2003; 278(7):5001–5008.
Takeshita S, Namba N, Zhao JJ et al. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med 2002; 8(9):943–949.
Rhee SG. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 2001; 70:281–312.
Mao D, Epple H, Uthgenannt B et al. PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest 2006; 116(11):2869–2879.
Takayanagi H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med 2005; 83(3):170–179.
Mocsai A, Humphrey MB, Van Ziffle JA et al. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci USA 2004; 101(16):6158–6163.
Laurin N, Brown JP, Morissette J et al. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 2002; 70(6):1582–1588.
Duran A, Serrano M, Leitges M et al. The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell 2004; 6(2):303–309.
Takayanagi H, Ogasawara K, Hida S et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 2000; 408(6812):600–605.
Takayanagi H, Kim S, Matsuo K et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 2002; 416(6882):744–749.
Syed F, Khosla S. Mechanisms of sex steroid effects on bone. Biochem Biophys Res Commun 2005; 328(3):688–696.
Nakamura T, Imai Y, Matsumoto T et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 2007; 130(5):811–823.
Abu-Amer Y. IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB. J Clin Invest 2001; 107(11):1375–1385.
Koseki T, Gao Y, Okahashi N et al. Role of TGF-beta family in osteoclastogenesis induced by RANKL. Cell Signal 2002; 14(1):31–36.
Ross FP, Teitelbaum SL. Alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev 2005; 208:88–105.
Arai F, Miyamoto T, Ohneda O et al. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med 1999; 190(12):1741–1754.
Kong YY, Feige U, Sarosi I et al. Activated T-cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402(6759):304–309.
Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 2005; 5(6):618–625.
Wittrant Y, Theoleyre S, Chipoy C et al. RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 2004; 1704(2):49–57.
McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354(8):821–831.
Lane NE, Iannini M, Atkins C et al. RANKL inhibition with denosumab decreases markers of bone and cartilage turnover in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54(Suppl 9):S225–226.
Dore R, Hurd E, Palmer W et al. Denosumab increases bone mineral density in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54(Suppl 9):S240.
Cohen SB, Valen P, Ritchlin C et al. RANKL inhibition with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: Month 6 MRI results. Arthritis Rheum 2006; 54(Suppl 9):S831–832.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Leibbrandt, A., Penninger, J.M. (2009). RANKL/RANK as Key Factors for Osteoclast Development and Bone Loss in Arthropathies. In: López-Larrea, C., Díaz-Peña, R. (eds) Molecular Mechanisms of Spondyloarthropathies. Advances in Experimental Medicine and Biology, vol 649. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0298-6_7
Download citation
DOI: https://doi.org/10.1007/978-1-4419-0298-6_7
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-0297-9
Online ISBN: 978-1-4419-0298-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)