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The Osteoclast

  • Chapter
The Macrophage as Therapeutic Target

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 158))

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Abstract

The osteoclast is the cell that resorbs bone. It has been known for many years that it is formed from cells of the mononuclear phagocyte system, and that its formation and function are governed by osteoblastic cells. Recently, the molecular basis for this regulation was identified: osteoblastic cells induce osteoclastic differentiation in immature mononuclear phagocytes through expression of macrophage colony-stimulating factor (M-CSF) and receptor-activator of NFкB ligand (RANKL). Osteoblastic regulation of bone resorption is assisted through secretion of an inhibitor, osteoprotegerin (OPG), a soluble (decoy) receptor for RANKL. Transforming growth factor beta (TGF-β), which is present in bone matrix in large amounts, is also essential for osteoclast formation, at least in vitro. Surprisingly, TNF-α can substitute for and is strongly synergistic with RANKL for osteoclast-induction. TNF-α is widely expressed, and RANKL can also be present in situations that are not associated with osteoclast formation, so that the presence of large quantities of TGF-β in bone matrix might explain why osteoclast formation is essentially confined to the bone microenvironment. In this review, recent data concerning the mechanisms underlying the induction of osteoclastic differentiation and function are described, together with recent findings concerning the mechanisms through which osteoclasts adhere to and resorb bone. Several of these mechanisms are currently being exploited for the development of novel therapies for diseases, such as osteoporosis, that are caused by excessive bone resorption.

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Abbreviations

α v β3:

β3integrin alpha v beta 3

CTR:

calcitonin receptor

M-CSF:

macrophage colony-stimulating factor

MMP:

matrix metalloproteinase

OPG:

osteoprotegerin

RANK:

receptor activator for NF-κB

RANKL:

ligand for RANK

TRAF :

TNF receptor-associated factor

TRAP:

tartrate-resistant acid phosphatase

TRANCE:

tumour necrosis factor-related activation-induced cytokine

References

  • 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: 175–179

    PubMed  CAS  Google Scholar 

  • Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, Miyata T, Anderson DM, Suda T (1999) Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor КB (RANK) receptors. J Exp Med 190: 1741–1754

    PubMed  CAS  Google Scholar 

  • Athanasou NA (1996) Current concepts review: Cellular biology of bone-resorbing cells. J Bone Joint Surg 78-A: 1096–1112

    Google Scholar 

  • Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A (2000) Tumor necrosis factor-α induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275: 4858–4864

    PubMed  CAS  Google Scholar 

  • Baron R, Neff L, Louvard D, Courtoy PJ (1985) Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100kD lysosomal membrane protein at the osteoclast ruffled border. J Cell Biol 101: 2210–2222

    PubMed  CAS  Google Scholar 

  • Boissy P, Destaing O, Jurdic P (2001) RANKL induces formation of avian osteoclasts from macrophages but not from macrophage polykaryons. Biochem Biophys Res Comm 288: 340–346

    PubMed  CAS  Google Scholar 

  • Brady KP, Dushkin H, Fornzler D, Koike T, Magner F, Her H, Gullan S, Segre GV, Green RM, Beier DR (1999) A novel putative transport maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics 56: 254–261

    PubMed  CAS  Google Scholar 

  • Buhling F, Reisenauer A, Gerber A, Kruger S, Weber E, Bromme D, Roessner A, Ansorge S, Weite T, Rocken C (2001) Cathepsin K-a marker of macrophage differentiation? J Pathol 195: 375–382

    PubMed  CAS  Google Scholar 

  • Burgess TL, Qian Y-X, Kaufman S, Ring BD, Van G, Capparelli C, Kelly M, Hsu H, Boyle WJ, Dunstan CJ, Hu S, Lacey DL (1999) The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 145: 527–538

    PubMed  CAS  Google Scholar 

  • Chambers TJ (1980) The cellular basis of bone resorption. Clin Orthop Rel Res 151: 283–293

    Google Scholar 

  • Chambers TJ (1982) Osteoblasts release osteoclasts from calcitonin-induced quiescence. J Cell Sci 57: 247–260

    PubMed  CAS  Google Scholar 

  • Chambers TJ (1985) The pathobiology of the osteoclast. J Clin Pathol 38: 241–252

    PubMed  CAS  Google Scholar 

  • Chambers TJ (1989) The origin of the osteoclast. In: Peck W (ed(s) Bone and Mineral Research Annual, vol. 6. Elsevier, Amsterdam, p 1–25

    Google Scholar 

  • Chambers TJ (1992) Regulation of osteoclast development and function. In: Rifkin BR, Gay CV (ed(s) Biology and Physiology of the Osteoclast. CRC Press, Boca Raton, p 105–128

    Google Scholar 

  • Chambers TJ (2000) Regulation of the differentiation and function of osteoclasts. J Pathol 192: 4–13

    PubMed  CAS  Google Scholar 

  • Chambers TJ, Darby JA, Fuller K (1985) Mammalian collagenase predisposes bone surfaces to osteoclastic resorption. Cell Tiss Res 241: 671–675

    CAS  Google Scholar 

  • Chambers TJ, Fuller K (1985) Bone cells predispose bone surfaces to resorption by exposure of mineral to osteoclastic contact. J Cell Sci 76: 155–165

    PubMed  CAS  Google Scholar 

  • Chambers TJ, Fuller K, Darby JA, Pringle JAS, Horton MA (1986) Monoclonal antibodies against osteoclasts inhibit bone resorption in vitro. Bone Miner 1: 127–135

    PubMed  CAS  Google Scholar 

  • Chambers TJ, Horton MA (1984) Failure of cells of the mononuclear phagocyte series to resorb bone. Calcif Tissue Int 36: 556–558

    PubMed  CAS  Google Scholar 

  • Chambers TJ, Revell PA, Fuller K, Athanasou NA (1984a) Resorption of bone by isolated rabbit osteoclasts. J Cell Sci 66: 383–399

    PubMed  CAS  Google Scholar 

  • Chambers TJ, Thomson BM, Fuller K (1984b) Effect of substrate composition on bone resorption by rabbit osteoclasts. J Cell Sci 70: 61–71

    PubMed  CAS  Google 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-termi-nal kinase. J Biol Chem 273: 20551–20555

    PubMed  CAS  Google Scholar 

  • Delaisse J-M, Boyde A, Maconnachie E, Ali NN, Sear CHJ, Eeckhout Y, Vaes G, Jones SJ (1987) The effects of inhibitors of cysteine-proteinases and collagenase on the re-sorptive activity of isolated osteoclasts. Bone 8: 305–313

    PubMed  CAS  Google Scholar 

  • Diaz A, Willis AC, Sim RB (2000) Expression of the proteinase specialized in bone resorption, cathepsin K, in granulomatous inflammation. Mol Med 6: 648–659

    PubMed  CAS  Google Scholar 

  • Drake FH, Dodds RA, James IE, Connor JR, Debouck C, Richardson S, Lee-Rykaczewski E, Coleman L, Rieman D, Barthlow R, Hastings G, Gowen M (1996) Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 271: 12511–12516

    PubMed  CAS  Google Scholar 

  • Fisher JE, Caulfield MP, Sato M, Quaruccio HA, Gould RJ, Garsky VM, Rodan GA, Rosenblatt M (1993) Inhibition of osteoclastic bone resorption in vivo by echistatin, an ’ar-ginyl-glycyl-aspartyl’ (RGD)-containing protein. Endocrinology 132: 1411–1413

    PubMed  CAS  Google Scholar 

  • Fox SW, Fuller K, Bayley KE, Lean JM, Chambers TJ (2000) TGF-ß1 and IFN-γ direct macrophage activation by TNF-α to osteoclastic or cytocidal phenotype. J Immunol 165: 4957–4963

    PubMed  CAS  Google Scholar 

  • Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Anders-son A-K, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Gen 25: 343–346

    CAS  Google Scholar 

  • Fuller K, Chambers TJ (1989) Bone matrix stimulates osteoclastic differentiation in cultures of rabbit bone marrow cells. J Bone Miner Res 4: 179–183

    PubMed  CAS  Google Scholar 

  • Fuller K, Chambers TJ (1995) Localisation of mRNA for collagenase in osteocytic, bone surface and chondrocytic cells but not osteoclasts. J Cell Sci 108: 2221–2230

    PubMed  CAS  Google Scholar 

  • Fuller K, Chambers TJ (1998) Parathyroid hormone induces bone resorption in human peripheral blood mononuclear cells. Int J Exp Pathol 79: 223–233

    PubMed  CAS  Google Scholar 

  • Fuller K, Lean JM, Bayley KE, Wani MR, Chambers TJ (2000) A role for TGF-ß1 in osteoclast differentiation and survival. J Cell Sci 113: 2445–2453

    PubMed  CAS  Google Scholar 

  • Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ (2002) TNFα potently activates osteoclasts, through a direct action independent of and strongly synergistic with RAN-KL. Endocrinology 143: In press

    Google 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: 997–1001

    PubMed  CAS  Google 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: 34120–34127

    PubMed  CAS  Google Scholar 

  • Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, Foged NT, Delmas PD, Delaisse J-M (1998) The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 273: 32347–32352

    PubMed  CAS  Google Scholar 

  • Gay CV, Mueller WJ (1974) Carbonic anhydrase and osteoclasts: Localization by labeled inhibitor autoradiography. Science 183: 432–434

    PubMed  CAS  Google Scholar 

  • Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273: 1236–1238

    PubMed  CAS  Google Scholar 

  • Gowen M, Emery JG, Kumar S (2000) Emerging therapies for osteoporosis. Emerging Drugs 5: 1–43

    CAS  Google Scholar 

  • Gowen M, Nedwin GE, Mundy GR (1986) Preferential inhibition of cytokine-stimulated bone resorption by recombinant interferon gamma. J Bone Miner Res 1: 469–474

    PubMed  CAS  Google Scholar 

  • Grigoriadis AE, Wang Z-Q, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF (1994) c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266: 443–448

    PubMed  CAS  Google Scholar 

  • Hall TJ, Chambers TJ (1989) Optimal bone resorption by isolated rat osteoclasts requires chloride/bicarbonate exchange. Calcif Tiss Int 45: 378–380

    CAS  Google Scholar 

  • Hall TJ, Higgins W, Tardif C, Chambers TJ (1991) A comparison of the effects of inhibitors of carbonic anhydrase on osteoclastic bone resorption and purified carbonic anhydrase isozyme II. Calcif Tissue Int 49: 328–332

    PubMed  CAS  Google Scholar 

  • Halleen JM, Räisänen S, Salo JJ, Reddy SV, Roodman GD, Hentunen TA, Lehenkari PP, Kaija H, Vihko P, Väänänen HK (1999) Intracellular fragmentation of bone resorption products by reactive oxygen species generated by tartrate-resistant acid phosphatase. J Biol Chem 274: 22907–22910

    PubMed  CAS  Google Scholar 

  • Hattersley G, Chambers TJ (1989) Generation of osteoclasts from hemopoietic cells and a multipotential cell line in vitro. J Cell Physiol 140: 478–482

    PubMed  CAS  Google Scholar 

  • Hattersley G, Chambers TJ (1990) Effects of interleukin 3 and of granulocyte-macrophage and macrophage colony stimulating factors on osteoclast differentiation from mouse hemopoietic tissue. J Cell Physiol 142: 201–209

    PubMed  CAS  Google Scholar 

  • Hattersley G, Owens J, Flanagan AM, Chambers TJ (1991) Macrophage colony stimulating factor (M-CSF) is essential for osteoclast formation in vitro. Biochem Biophys Res Comm 177: 526–531

    PubMed  CAS  Google Scholar 

  • Helfrich MH, Horton MA (1993) Antigens of osteoclasts: phenotypic definition of a specialized hemopoietic cell lineage. In: Horton MA (ed(s) Blood Cell Biochemistry: Macrophages and Related Cells, vol. 5. Plenum Press, New York, p 183–202

    Google Scholar 

  • Hernando N, Bartkiewicz M, Collin-Osdoby P, Osdoby P, Baron R (1995) Alternative spicing generates a second isoform of the catalytic a subunit of the vacuolar H(+)-AT-Pase. Proc Natl Acad Sci USA 92: 6087–6091

    PubMed  CAS  Google Scholar 

  • Hofbauer LC, Lacey DL, Dunstan CR, Speisberg TC, Riggs BL, Khosla S (1999) Interleukin-Iß and tumor necrosis factor-α, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25: 255–259

    PubMed  CAS  Google Scholar 

  • Horton MA, Taylor ML, Arnett TR, Helfrich MH (1991) Arg-gly-asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts. Exp Cell Res 195: 368–375

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Horwood NJ, Elliott J, Martin TJ, Gillespie MT (2001) IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro. J Immunol 166: 4915–4921

    PubMed  CAS  Google Scholar 

  • Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RHG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Signal peptide mutations in RANK cause familial expansile osteolysis. Nat Gen 24: 45–49

    CAS  Google Scholar 

  • Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-KB1 and NF-KB2. Nat Med 3: 1285–1289

    PubMed  CAS  Google Scholar 

  • Ishibashi O, Inui T, Mori Y, Kurokawa T, Kokubo T, Kumegawa M (2001) Quantification of the expression levels of lysosomal cysteine proteinases in purified human osteoclastic cells by competitive RT-PCR. Calcif Tissue Int 68: 109–116

    PubMed  CAS  Google Scholar 

  • Iyer VR, Eisen MB, Rosse DT, Schuler G, Moore T, Lee JCF, Trent JM, Staudt LM, Hudson Jr J, Boguski MS, Lashkari D, Shalon D, Botstein D, Brown PO (1999) The transcriptional program in the response of human fibroblasts to serum. Science 283: 83–87

    PubMed  CAS  Google Scholar 

  • Johnson RS, Spiegelman BM, Papaioannou V (1992) Pleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell 71: 577–586

    PubMed  CAS  Google Scholar 

  • Kamiya T, Kobayashi Y, Kanaoka K, Nakashima T, Kato Y, Mizuno A, Sakai H (1998) Fluorescence microscopic demonstration of cathepsin K activity as the major lysosomal cysteine proteinase in osteoclasts. J Biochem 123: 752–759

    PubMed  CAS  Google Scholar 

  • Karsdal MA, Fjording MS, Foged NT, Delaissé J-M (2001) Transforming growth factor-ß-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogen-activated protein kinase- and matrix metalloproteinase-dependent pathway. J Biol Chem 276: 39350–39358

    PubMed  CAS  Google Scholar 

  • Kaye M (1984) When is it an osteoclast? J Clin Pathol 37: 398–400

    PubMed  CAS  Google Scholar 

  • Kim H-H, Lee DE, Shin JN, Lee YS, Jeon YM, Chung C-H, Ni J, 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: 297–302

    PubMed  CAS  Google Scholar 

  • Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T (2000) Tumor necrosis factor a stimulates osteoclastic differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191: 275–285

    PubMed  CAS  Google Scholar 

  • Kong Y-Y, Felge U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li JI, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402: 304–309

    PubMed  CAS  Google Scholar 

  • Kornak U, Kasper D, Bõsl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch T (2001) Loss of the CIC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104: 205–215

    PubMed  CAS  Google Scholar 

  • Lacey DL, Erdmann JM, Teitelbaum SL, Tan H-L, Ohara J, Shioi A (1995) Interleukin 4, interferon-γ, and prostaglandin E impact the osteoclast cell-forming potential of murine bone marrow macrophages. Endocrinology 136: 2367–2376

    PubMed  CAS  Google Scholar 

  • Lagasse E, Weissman IL (1997) Enforced expression of Bcl-2 in monocytes rescues macrophages and partially reverses osteopetrosis in op/op mice. Cell 89: 1021–1031

    PubMed  CAS  Google Scholar 

  • Lakkakorpi PT, Horton MA, Helfrich MH, Karhukorpi E-K, Väänänen HK (1991) Vitronectin receptor has a role in bone resorption but does not mediate tight sealing zone attachment of osteoclasts to the bone surface. J Cell Biol 115: 1179–1186

    PubMed  CAS  Google Scholar 

  • Lean JM, Fuller K, Chambers TJ (2001) Flt3 ligand can substitute for M-CSF in support of osteoclast differentiation and function. Bloodln press

    Google Scholar 

  • Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-ß. Ann Rev Immunol 16: 137–161

    CAS  Google Scholar 

  • Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan SC, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, MKostenuik P, Hsu H, Fletcher F, Dunstan CR, Lacey DL, Boyle WJ (2000a) 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: 1566–1571

    PubMed  CAS  Google Scholar 

  • Li Y-P, Chen W, Liang Y, Li E, Stashenko P (1999) Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Gen 23: 447–451

    CAS  Google Scholar 

  • Li Y-P, Chen W, Stashenko P (1996) Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit. Biochem Biophys Res Comm 218: 813–821

    PubMed  CAS  Google Scholar 

  • Li Z, Hou WS, Bromme D (2000b) Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 39: 529–536

    PubMed  CAS  Google Scholar 

  • Liu BY, Guo J, Lanske B, Divieti P, Kronenberg HM, Bringhurst FR (1998) Conditionally immortalised murine bone marrow stromal cells mediate parathyroid hormone-dependent osteoclastogenesis in vitro. Endocrinology 139: 1952–1964

    PubMed  CAS  Google Scholar 

  • Lomaga MA, Yeh W-C, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Develop 13: 1015–1024

    PubMed  CAS  Google Scholar 

  • Marks SC (1983) The origin of the osteoclast. J Oral Pathol 12: 226–256

    PubMed  Google Scholar 

  • Masarachia P, Yamamoto M, Leu C, Rodan G, Duong L (1998) Histomorphometric evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism. Endocrinology 139: 1401–1410

    PubMed  CAS  Google Scholar 

  • Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF (2000) Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Gen 24: 184–187

    CAS  Google Scholar 

  • Matsuzaki K, Katayama K, Takahashi Y, Nakamura Y, Udagawa N, Tsurukai T, Nishinaka-mura R, Toyama Y, Yasbe Y, Hori M, Takahashi N, Suda T (1998) Human osteoclast-like cells are formed from peripheral blood mononuclear cells in a co-culture with SaOS-2 cells transfected with the PTH/PTHrP receptor gene. Endocrinology 140: 925–932

    Google Scholar 

  • McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Ross FX, Hynes RO, Teitelbaum SL (2000) Mice lacking ß3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105: 433–440

    PubMed  CAS  Google Scholar 

  • McSheehy PMJ, Chambers TJ (1986) Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endocrinology 118: 824–828

    PubMed  CAS  Google Scholar 

  • Miyamoto T, Ohneda O, Arai F, Iwamoto K, Okada S, Takagi K, Anderson DM, Suda T (2001) Bifurcation of osteoclasts and dendritic cells from common progenitors. Blood 98: 2544–2554

    PubMed  CAS  Google Scholar 

  • Möst J, Spötl L, Mayr G, Gasser A, Sarti A, Dierich MP (1997) Formation of multinucleated giant cells in vitro is dependent on the stage of monocyte to macrophage maturation. Blood 89: 662–671

    PubMed  Google Scholar 

  • Murakami T, Yamamoto M, Yamamoto M, Ono K, Nishikawa M, Nagata N, Motoyoshi K, Akatsu T (1998) Transforming growth factor-ßl 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: 747–752

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Nakamura I, Pilkington MF, Lakkakorpi PT, Lipfert L, Sims SM, Dixon SJ, Rodan GA, Duong LT (1999) Role of αvß3 integrin in osteoclast migration and formation of the sealing zone. J Cell Sci 112: 3985–3993

    PubMed  CAS  Google Scholar 

  • Nakamura I, Takahashi N, Udagawa N, Moriyama Y, Kurokawa T, Jimi E, Sasaki T, Suda T (1997) Lack of vacuolar proton ATPase association with the cytoskeleton in osteoclasts of osteosclerotic mice (oc/oc) mice. FEBS Lett 401: 207–212

    PubMed  CAS  Google 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: 1689–1699

    PubMed  CAS  Google Scholar 

  • Popoff SN, Marks Jr SC (1986) Ultrastructure of the giant cell infiltrate of subcutaneously implanted bone particles in rats and mice. Am J Anat 177: 491–503

    PubMed  CAS  Google Scholar 

  • Prallet B, Male P, Neff L, Baron R (1992) Identification of a functional mononuclear precursor of the osteoclast in chicken medullary bone-marrow cultures. J Bone Miner Res 7: 405–414

    PubMed  CAS  Google Scholar 

  • Quinn JMW, McGee JOD, Athanasou NA (1994) Cellular and hormonal factors influencing monocyte differentiation to osteoclastic bone-resorbing cells. Endocrinology 134: 2416–2423

    PubMed  CAS  Google Scholar 

  • Reponen P, Sahlberg C, Muhnaut C, Thesleff I, Tryggvason K (1994) High expression of 92-kD type IV collagenase (gelatinase B) in the osteoclast lineage during mouse development. J Cell Biol 124: 1091–1102

    PubMed  CAS  Google Scholar 

  • Riches DWH (1996) Macrophage involvement in wound repair, remodeling, and fibrosis. In: Clark RAF (ed(s) The Molecular and Cellular Biology of Wound Repair. Plenum Press, New York, p 95–141

    Google Scholar 

  • Rodan GA, Martin TJ (1981) The role of osteoblasts in hormonal control of bone resorption. Calcif Tiss Int 33: 349–351

    CAS  Google Scholar 

  • Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289: 1508–5014

    PubMed  CAS  Google Scholar 

  • Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 95: 13453–13458

    PubMed  CAS  Google Scholar 

  • Schlesinger PH, Blair HC, Teitelbaum SL, Edwards JC (1997) Characterization of the osteoclast ruffled border chloride channel and its role in bone resorption. J Biol Chem 272: 18636–18643

    PubMed  CAS  Google Scholar 

  • Scimeca J-C, Franchi A, Trojani C, Parrinello H, Grosgeorge J, Robert C, Jaillon O, Poirier C, Gaudray P, Carle GF (2000) The gene encoding the mouse homologue of the human osteoclast-specific 116 kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone 26: 207–213

    PubMed  CAS  Google Scholar 

  • Sells Galvin RJ, Gatlin CL, Horn JW, Fuson TR (1999) TGF-beta enhances osteoclast differentiation in hematopoietic cell cultures stimulated with RANKL and M-CSF. Bio-chem Biophys Res Comm 265: 233–239

    Google Scholar 

  • Silver IA, Murrills RJ, Etherington DJ (1988) Microelectrode studies on the acid microen-vironment beneath adherent macrophages and osteoclasts. Exp Cell Res 175: 266–276

    PubMed  CAS  Google Scholar 

  • Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Columbero A, Tan H-L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Program. AE, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: 309–319

    PubMed  CAS  Google Scholar 

  • Sly WS, Hewett-Emmett D, Whyte MP, Yu Y-SL, Tashjian RE (1983) Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci USA 80: 2752–2756

    PubMed  CAS  Google Scholar 

  • Stenbeck G, Horton MA (2000) A new specialized cell-matrix interaction in actively resorbing osteoclasts. J Cell Sci 113: 1577–1587

    PubMed  CAS  Google Scholar 

  • Suda T, Takahashi N, Martin TJ (1995) Modulation of osteoclast differentiation: update. In: Bikle DD, Negrovilar A (ed(s) Endoc Rev Monographs, vol. 4. Endocrine Society, Bethesda, MD, p 266–270

    Google Scholar 

  • Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new member of the tumor necrosis factor receptor and ligand families. Endocr Rev 20: 345–357

    PubMed  CAS  Google Scholar 

  • Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T (1988) Osteoblastic cells are involved in osteoclast formation. Endocrinology 123: 2600–2602

    PubMed  CAS  Google Scholar 

  • Takahashi N, Udagawa N, Akatsu T, Tanaka H, Isogai Y, Suda T (1991) Deficiency of osteoclasts in osteopetrotic mice is due to a defect in the local microenvironment provided by osteoblastic cells. Endocrinology 128: 1792–1796

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T (2000) T-cell-mediated regulation of os- teoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 408: 600–605

    PubMed  CAS  Google Scholar 

  • Takeda S, Yoshizawa T, Nagai Y, Yamato H, Fukumoto S, Sekine K, Kato S, Matsumoto T, Fujita T (1999) Stimulation of osteoclast formation by 1,25-dihydroxyvitamin D requires its binding to vitamin D receptor (VDR) in osteoblastic cells: studies using VDR knockout mice. Endocrinology 140: 1005–1008

    PubMed  CAS  Google Scholar 

  • Tezuka K-i, Tezuka Y, Maejima A, Sato T, Nemoto K, Kamioka H, Hakeda Y, Kumegawa M (1994) Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem 269: 1106–1109

    PubMed  CAS  Google Scholar 

  • Thomson BM, Mundy GR, Chambers TJ (1987) Tumor necrosis factors a and ß induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol 138: 775–779

    PubMed  CAS  Google Scholar 

  • Thomson BM, Saklatvala J, Chambers TJ (1986) Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts. J Exp Med 164: 104–112

    PubMed  CAS  Google Scholar 

  • Thyberg J (1996) Differentiated properties and proliferation of arterial smooth muscle cells in culture. Int Rev Cytol 169: 183–265

    PubMed  CAS  Google Scholar 

  • Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K (1997) Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclas-togenesis. Biochem Biophys Res Comm 234: 137–142

    PubMed  CAS  Google Scholar 

  • Udagawa N, Horwood NJ, Elliott J, Mackay A, Owens J, Okamura H, Kurimoto M, Chambers TJ, Martin TJ, Gillespie MT (1997) Interleukin (IL)-18 (interferon gamma inducing factor) is produced by osteoblasts and acts via granulocyte macrophage-colony stimulating factor and not via interferon-gamma to inhibit osteoclast formation. J Exp Med 185: 1005–1012

    PubMed  CAS  Google Scholar 

  • Väänänen HK, Zhao H, Mulari M, Halleen JM (2000) The cell biology of osteoclast function. J Cell Sci 113: 377–381

    PubMed  Google Scholar 

  • Vaananen JK, Karhukorpi EK, Sundquist K, Wallmark B, Hentunen T, Tuukanen J, Lakkakorpi P (1990) Evidence for the presence of a proton pump of the vacuolar H+- ATPase type in the ruffled borders of osteoclasts. J Cell Biol 111: 1305–1311

    PubMed  CAS  Google Scholar 

  • Van Hille B, Richener H, Green JR, Bilbe G (1995) The ubiquitous VA68 isoform of subunit A of the vacuolar H(+)-ATPase is highly expressed in human osteoclasts. Biochem Biophys Res Comm 214: 1108–1113

    PubMed  Google Scholar 

  • Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93: 411–422

    PubMed  CAS  Google Scholar 

  • Wang Z-Q, Ovitt C, Grigoriadis AE, Mohle-Steinlen U, Rüther U, Wagner EF (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360: 741–745

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW, Jr., Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colony-stimulating factor 1 in the macro-phage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832

    PubMed  CAS  Google Scholar 

  • Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett III FS, Frankel WN, Lee SY, Choi Y (1997) 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 272: 25190–25194

    PubMed  CAS  Google Scholar 

  • Xia L, Kilb J, Wex H, Li Z, Lipyansky A, Breuil V, Stein L, Palmer JT, Dempster DW, Bromme D (1999) Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption and cathepsin-K activity by peptidyl vinyl sulfones. Biol Chem 380: 679–687

    PubMed  CAS  Google Scholar 

  • Yamamoto M, Fisher JE, Gentile M, Seedor JG, Leu C-T, Rodan SB, Rodan GA (1998) The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats. Endocrinology 139: 1411–1419

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Zhao W, Byrne MH, Boyce BF, Krane SM (1999) Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice. J Clin Invest 103: 517–524

    PubMed  CAS  Google Scholar 

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  1. Department of Cellular Pathology, St. George’s Hospital Medical School, Cranmer Terrace, SW17 0RE, London, UK

    T. J. Chambers

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK

    Siamon Gordon

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Chambers, T.J. (2003). The Osteoclast. In: Gordon, S. (eds) The Macrophage as Therapeutic Target. Handbook of Experimental Pharmacology, vol 158. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55742-2_19

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  • DOI: https://doi.org/10.1007/978-3-642-55742-2_19

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