Abstract
NF-κB and c-Fos are transcription factors that are activated in immune cells and in most other cell types following stimulation by a variety of factors, including cytokines, growth factors, and hormones. They regulate the expression of a large number of genes, and both are activated in osteoclast precursors after RANKL, IL-1, or TNF bind to their respective receptors. However, of these cytokines, only RANKL is required for the induction of osteoclast formation in vivo. Nevertheless, it is likely that IL-1, TNF, and other cytokines participate in the upregulation of osteoclast formation seen in a variety of conditions that affect the skeleton in which cytokine production is increased, including estrogen deficiency and inflammatory bone diseases. In this review, the RANKL/ OPG/RANK system and roles for NF-κB and c-Fos in osteoclasts are reviewed along with our current understanding of how this system may be disrupted in common bone diseases, such as postmenopausal osteoporosis, inflammatory arthritis, and Paget’s disease.
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References
Rasmussen H, Bordier P (1974) The Physiological Basis of Metabolic Bone Disease. William & Wilkins, Baltimore, USA, pp 1–314
Kahn AJ, Simmons DJ (1975) Investigation of cell lineage in bone using a chimaera of chick and quial embryonic tissue. Nature (Lond) 258: 325–327
Walker DG (1975) Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science 190: 784–785
Raisz LG, Luben RA, Mundy GR, Dietrich JW, Horton JE, Trummel CL (1975) Effect of osteoclast activating factor from human leukocytes on bone metabolism. J Clin Invest 56: 408–413
Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693–702
Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR (1992) Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest 90: 1622–1627
Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U (1997) Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 11: 3482–3496
Iotsova V, Caamano J, Loy J, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-κB1 and NF-KB2. Nat Med 3: 1285–1289
Simonet WS, Lacey DL, Dunstan CR, et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: 309–319
Lacey DL, Timms E, Tan HL, et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: 165–176
Li J, Sarosi I, Yan XQ, 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 U S A 97: 1566–1571
Dougall WC, Glaccum M, Charrier K, Brasel KR, Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Schuh JP (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13: 2412–2424
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature (Lond) 397: 315–323
Kong YY, Feige U, Sarosi I, et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature (Lond) 402: 304–309
Itonaga I, Fujikawa Y, Sabokbar A, Murray DW, Athanasou NA (2000) Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol 192: 97–104
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: 4367–4370
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 Commun 250: 776–781
Atkins GJ, Kostakis P, Pan B, Farrugia A, Gronthos S, Evdokiou A, Harrison K, Findlay DM, Zannettino AC (2003) RANKL expression is related to the differentiation state of human osteoblasts. J Bone Miner Res 18: 1088–1098
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature (Lond) 423: 337–342
Hayden MS, Ghosh S (2004) Signaling to NF-kappa B. Genes Dev 18: 2195–2224
Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F, Boyce BF (2002) NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis. J Bone Miner Res 17: 1200–1210
Siebelist U, Franzoso G, Brown K (1994) Structure, regulation and function of NF-κB. Annu Rev Cell Biol 10: 405–455
Baldwin A (2001) The transcription factor NF-κB and human disease. J Clin Invest 107: 3–6
Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV, Ross FP, Teitelbaum SL (2003) The IkappaB function of NF- kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med 198: 771–781
Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4: E131-E136
Wang Z-Q, OVitt C, Grigoriadis AE, Mohle-Steinlein U, Ruther U, Wagner EF (1992) Bone and haematopoietic defects in mice lacking c-Fos. Nature (Lond) 360: 741–745
Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109(suppl): S67-S79
Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15: 707–747
Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T (2002) Induction and activation of the transcription factor NFATcl (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3: 889–901
Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature (Lond) 428: 758–763
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: 41147–41156
Hirotani H, Tuohy NA, Woo JT, Stern PH, Clipstone NA (2004) The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J Biol Chem 279: 13984–13992
Matsuo K, Galson DL, Zhao C, Peng L, Laplace C, Wang KZ, Bachler MA, Amano H, Aburatani H, Ishikawa H, Wagner EF (2004) Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem 279: 26475–26480
Igarashi K, Hirotani H, Woo JT, Stern PH (2004) Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow cell cultures. Bone 35: 47–56
Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda T (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114: 475–484
McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE (2002) Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109: 707–718
Rajapurohitam V, Chalhoub N, Benachenhou N, Neff L, Baron R, Vacher J (2001) The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation/function. Bone 28: 513–523
Partington GA, Fuller K, Chambers TJ, Pondel M (2004) Mitf- PU.l interactions with the tartrate-resistant acid phosphatase gene promoter during osteoclast differentiation. Bone 34: 237–245
Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14: 1654–1663
Hofbauer LC, Heufelder AE (1999) Osteopetrosis in cathepsin K-deficient mice. Eur J Endocrinol 140: 376–377
Hayman AR, Jones SJ, Boyde A, Foster D, Colledge WH, Carlton MB, Evans MJ, Cox TM (1996) Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development (Camb) 122: 3151–3162
Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J (2003) Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 9: 399–406
Boyce BF (2003) Bad bones, grey hair, one mutation. Nat Med 9: 395–396
Wong B, Besser D, Kim N, Arron J, Vologodskaia M, Hanafusa H, Choi Y (1999) TRANCE, a TNF family member, activates Akt/ PKB through a signaling complex involving TRAF6 and c-Src. Cell 4: 1041–1049
Xing L, Venegas AM, Chen A, Garrett-Beal L, Boyce BF, Varmus HE, Schwartzberg PL (2001) Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev 15: 241–253
Recchia I, Rucci N, Funari A, Migliaccio S, Taranta A, Longo M, Kneissel M, Susa M, Fabbro D, Teti A (2004) Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway. Bone 34: 65–79
Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, Pando MP, Asano T, Verma IM, Oda H, Nakamura K, Tanaka S (2000) Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol 148: 333–342
Gingery A, Bradley E, Shaw A, Oursler MJ (2003) Phosphatidylinositol 3-kinase coordinately activates the MEK/ ERK and AKT/NFkappaB pathways to maintain osteoclast survival. J Cell Biochem 89: 165–179
Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T (2002) RANKL maintains bone homeostasis through c-Fosdependent induction of interferon-beta [see comment]. Nature (Lond) 416: 744–749
Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature (Lond) 423: 356–361
Yao Z, Li P, Zhang Q, Schwarz EM, Ma L, Keng P, Boyce BF, Xing LP (2004) TNF increases bone marrow osteoclast precursor numbers by stimulating their proliferation and differentiation through up-regulation of c-Fms expression. J Bone Miner Res 19: S171
Li P, Schwarz EM, O’Keefe RJ, Ma L, Looney RJ, Ritchlin CT, Boyce BF, Xing L (2004) Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11b high osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum 50: 265–276
Li P, Schwarz EM, O’Keefe RJ, Ma L, Boyce BF, Xing L (2004) RANK signaling is not required for TNFa-mediated increase in CD11bhi osteoclast precursors, but is essential for mature osteoclast formation in TNFa-mediated inflammatory arthritis. J Bone Miner Res 19: 207–213
Yamashita T, Xing L, Li P, Schwarz EM, Dougall WC, Boyce BF (2002) c-Fos over-expression induces osteoclastogenesis independent of RANK signaling. J Bone Miner Res 17: S131
Yamashita T, Xing L, Matsuo K, Wagner EF, Boyce BF (2003) Treatment of c-Fos over-expressing osteoclast precursors with cytokines induces osteoclastformation and abrogates bisphosphonate-induced osteoclast apoptosis. J Bone Miner Res 18: S17
Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-13. Nat Med 2: 1132–1136
Locklin RM, Khosla S, Turner RT, Riggs BL (2003) Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone. J Cell Biochem 89: 180–190
Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349: 1207–1215
Reddy SV, Kurihara N, Menaa C, Roodman GD (2001) Paget’s disease of bone: a disease of the osteoclast. Rev Endocr Metab Disord 2: 195–201
Johnson-Pais TL, Wisdom JH, Weldon KS, Cody JD, Hansen MF, Singer FR, Leach RJ (2003) Three novel mutations in SQSTM1 identified in familial Paget’s disease of bone. J Bone Miner Res 18: 1748–1753
Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH (2002) Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet 11: 2735–2739
Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24: 45–48
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Boyce, B.F., Yamashita, T., Yao, Z. et al. Roles for NF-κB and c-Fos in osteoclasts. J Bone Miner Metab 23 (Suppl 1), 11–15 (2005). https://doi.org/10.1007/BF03026317
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DOI: https://doi.org/10.1007/BF03026317