Abstract
Collagen-induced arthritis (CIA) in mice is accompanied by splenomegaly due to the selective expansion of immature CD11b+ myeloblasts. Both disease manifestations are more pronounced in interferon-γ receptor knock-out (IFN-γR KO) mice. We have taken advantage of this difference to test the hypothesis that the expanding CD11b+ splenic cell population constitutes a source from which osteoclast precursors are recruited to the joint synovia. We found larger numbers of osteoclasts and more severe bone destruction in joints of IFN-γR KO mice than in joints of wild-type mice. Osteoclast-like multinucleated cells appeared in splenocyte cultures established in the presence of macrophage colony-stimulating factor (M-CSF) and stimulated with the osteoclast-differentiating factor receptor activator of NF-κB ligand (RANKL) or with tumour necrosis factor-α (TNF-α). Significantly larger numbers of such cells could be generated from splenocytes of IFN-γR KO mice than from those of wild-type mice. This was not accompanied, as might have been expected, by increased concentrations of the intracellular adaptor protein TRAF6, known to be involved in signalling of RANKL- and TNF-α-induced osteoclast formation. Splenocyte cultures of IFN-γR KO mice also produced more TNF-α and more RANKL than those of wild-type mice. Finally, splenocytes isolated from immunised IFN-γR KO mice contained comparatively low levels of pro-interleukin-1β (pro-IL-1β) and pro-caspase-1, indicating more extensive conversion of pro-IL-1β into secreted active IL-1β. These observations provide evidence that all conditions are fulfilled for the expanding CD11b+ splenocytes to act as a source of osteoclasts and to be indirectly responsible for bone destruction in CIA. They also provide a plausible explanation for the higher susceptibility of IFN-γR KO mice to CIA.
Similar content being viewed by others
Abbreviations
- BMM:
-
bone marrow macrophage
- BSA:
-
bovine serum albumin
- cDNA:
-
complementary DNA
- CFA:
-
complete Freund's adjuvant
- CIA:
-
collagen-induced arthritis
- CII:
-
collagen type II
- ELISA:
-
enzyme-linked immunosorbent assay
- IFN-γ:
-
interferon-γ
- IFN-γR KO:
-
interferon-γ receptor knock-out
- IL:
-
interleukin
- M-CSF:
-
macrophage colony-stimulating factor
- ODF:
-
osteoclast differentiation factor
- OPG:
-
osteoprotegerin
- OPGL:
-
osteoprotegerin ligand
- PBS:
-
phosphate-buffered saline
- PCR:
-
polymerase chain reaction
- RANK:
-
receptor activator of NF-κB
- RANKL:
-
receptor activator of NF-κB ligand
- TBS:
-
Tris-buffered saline
- TNF:
-
tumour necrosis factor
- TRAF:
-
TNF receptor associated factor
- TRANCE:
-
TNF-related activation-induced cytokine
- TRAP:
-
tartrate-resistant acid phosphatase.
References
Manoury-Schwartz B, Chiocchia G, Bessis N, Abehsira-Amar O, Batteux F, Muller S, Huang S, Boissier M-C, Fournier C: High susceptibility to collagen-induced arthritis in mice lacking IFN-γ receptors. J Immunol. 1997, 158: 5501-5506.
Vermeire K, Heremans H, Vandeputte M, Huang J, Billiau A, Matthys P: Accelerated collagen-induced arthritis in interferon-γ receptor-deficient mice. J Immunol. 1997, 158: 5507-5513.
Matthys P, Vermeire K, Mitera T, Heremans H, Huang J, Schols D, Dewolf-Peeters C, Billiau A: Enhanced autoimmune arthritis in IFN-γ receptor-deficient mice is conditioned by mycobacteria in Freund's adjuvant and by increased expansion of Mac-1+ myeloid cells. J Immunol. 1999, 163: 3503-3510.
Kronenberg HM: Developmental regulation of the growth plate. Nature. 2003, 423: 332-336. 10.1038/nature01657.
Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature. 2003, 423: 337-342. 10.1038/nature01658.
Harada S, Rodan GA: Control of osteoblast function and regulation of bone mass. Nature. 2003, 423: 349-355. 10.1038/nature01660.
Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 2003, 423: 356-361. 10.1038/nature01661.
Suzuki Y, Nishikaku F, Nakatuka M, Koga Y: Osteoclast-like cells in murine collagen induced arthritis. Endocr Rev. 1998, 25: 1154-1160.
Suda T, Takahashi N, Martin TJ: Modulation of osteoclast differentiation. Endocr Rev. 1992, 13: 66-80. 10.1210/er.13.1.66.
Roodman GD: Advances in bone biology: the osteoclast. Endocr Rev. 1996, 17: 308-332. 10.1210/er.17.4.308.
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998, 95: 3597-3602. 10.1073/pnas.95.7.3597.
Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y: 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: 25190-25194. 10.1074/jbc.272.40.25190.
Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998, 93: 165-176. 10.1016/S0092-8674(00)81569-X.
Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H: Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-κB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun. 2000, 275: 768-775. 10.1006/bbrc.2000.3379.
Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Caparelli C, 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: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999, 402: 304-309. 10.1038/46303.
Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR: Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000, 43: 250-258. 10.1002/1529-0131(200002)43:2<250::AID-ANR3>3.0.CO;2-P.
Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K, Morinaga T, Higashio K: RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998, 253: 395-400. 10.1006/bbrc.1998.9788.
Lubberts E, Oppers-Walgreen B, Pettit AR, Van Den BL, Joosten LA, Goldring SR, Gravallese EM, van den Berg WB: Increase in expression of receptor activator of nuclear factor κB at sites of bone erosion correlates with progression of inflammation in evolving collagen-induced arthritis. Arthritis Rheum. 2002, 46: 3055-3064. 10.1002/art.10607.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, 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, Boyle WJ: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997, 89: 309-319. 10.1016/S0092-8674(00)80209-3.
Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K: Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. 1997, 234: 137-142. 10.1006/bbrc.1997.6603.
Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y: Tumor necrosis factor-α (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem. 2001, 276: 563-568. 10.1074/jbc.M008198200.
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: Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000, 191: 275-286. 10.1084/jem.191.2.275.
Dinarello CA: Interleukin-1. Cytokine Growth Factor Rev. 1997, 8: 253-265. 10.1016/S1359-6101(97)00023-3.
Armstrong AP, Tometsko ME, Glaccum M, Sutherland CL, Cosman D, Dougall WC: A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem. 2002, 277: 44347-44356. 10.1074/jbc.M202009200.
Kaji K, Katogi R, Azuma Y, Naito A, Inoue JI, Kudo A: Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res. 2001, 16: 1593-1599.
Wu H, Arron JR: TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. BioEssays. 2003, 25: 1096-1105. 10.1002/bies.10352.
Takayanagi H, Kim S, Taniguchi T: Signaling crosstalk between RANKL and interferons in osteoclast differentiation. Arthritis Res Ther. 2002, 4 (Suppl 3): S227-S232. 10.1186/ar581.
Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S: The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. 1990, 345: 442-444. 10.1038/345442a0.
Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M: Immune response in mice that lack the interferon-γ receptor. Science. 1993, 259: 1742-1745.
Dijkmans R, Martens E, Beuken E, Cornette F, Dillen C, Heremans H, Boraschi D, Billiau A: Murine interferon-γ/interleukin-1 fusion protein used as antigens for the generation of hybridomas producing monoclonal anti-interleukin-1 antibodies. Cytokine. 1991, 3: 134-140. 10.1016/1043-4666(91)90034-B.
De Bari C, Dell'Accio F, Tylzanowski P, Luyten F: Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001, 44: 1928-1942. 10.1002/1529-0131(200108)44:8<1928::AID-ART331>3.0.CO;2-P.
Maes C, Carmeliet P, Moermans K, Stockmans I, Smets N, Collen D, Bouillon R, Carmeliet G: Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev. 2002, 111: 61-73. 10.1016/S0925-4773(01)00601-3.
Farrar MA, Schreiber RD: The molecular cell biology of interferon-γ and its receptor. Annu Rev Immunol. 1993, 11: 571-611. 10.1146/annurev.iy.11.040193.003035.
Matthys P, Hatse S, Vermeire K, Wuyts A, Bridger G, Henson G, De Clercq E, Billiau A, Schols D: AMD 3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-γ receptor-deficient mice. J Immunol. 2001, 167: 4686-4692.
Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T: T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature. 2000, 408: 600-605. 10.1038/35046102.
Huang W, O'Keefe RJ, Schwarz EM: Exposure to receptor-activator of NFκB ligand renders pre-osteoclasts resistant to IFN-γ by inducing terminal differentiation. Arthritis Res Ther. 2003, 5: R49-R59. 10.1186/ar612.
Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ: Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000, 103: 351-361. 10.1016/S0092-8674(00)00126-4.
Jensen LE, Whitehead AS: Ubiquitin activated tumor necrosis factor receptor associated factor-6 (TRAF6) is recycled via deubiquitination. FEBS Lett. 2003, 553: 190-194. 10.1016/S0014-5793(03)00998-0.
Lomaga MA, Yeh WC, 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: TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999, 13: 1015-1024.
Guedez YB, Whittington KB, Clayton JL, Joosten LAB, van de Loo FAJ, van den Berg WB, Rosloniec EF: Genetic ablation of interferon-γ up-regulates interleukin-1β expression and enables the elicitation of collagen-induced arthritis in a nonsusceptible mouse strain. Arthritis Rheum. 2001, 44: 2413-2424. 10.1002/1529-0131(200110)44:10<2413::AID-ART406>3.0.CO;2-E.
Joosten LA, Helsen MM, Saxne T, van de Loo FA, Heinegard D, van den Berg WB: IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol. 1999, 163: 5049-5055.
Finnegan A, Kaplan CD, Cao Y, Eibel H, Glant TT, Zhang J: Collagen-induced arthritis is exacerbated in IL-10-deficient mice. Arthritis Res Ther. 2003, 5: R18-R24. 10.1186/ar601.
Li P, Schwarz EM, O'Keefe RJ, Ma L, Looney RJ, Ritchlin CT, Boyce BF, Xing L: Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum. 2004, 50: 265-276. 10.1002/art.11419.
Matthys P, Vermeire K, Billiau A: Mac-1+ myelopoiesis induced by complete Freund's adjuvant (CFA): a clue to the paradoxical effects of IFN-γ in autoimmune disease models. Trends Immunol. 2001, 22: 367-371. 10.1016/S1471-4906(01)01937-8.
Acknowledgements
We thank Dr Lieve Moons for help in preparing histological slides, and Inge Derese for help in immunocytochemistry. Studies in the authors' laboratories are funded by the Concerted Research Actions (GOA) Initiative of the Regional Government of Flanders, the Interuniversity Attraction Pole Program (IUAP) of the Belgian Federal Government, and grants from the National Fund for Scientific Research of Flanders (FWO). PM holds a postdoctoral fellowship from the FWO.
Author information
Authors and Affiliations
Corresponding author
Additional information
Competing interests
None declared.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
Rights and permissions
About this article
Cite this article
De Klerck, B., Carpentier, I., Lories, R.J. et al. Enhanced osteoclast development in collagen-induced arthritis in interferon-γ receptor knock-out mice as related to increased splenic CD11b+myelopoiesis. Arthritis Res Ther 6, R220 (2004). https://doi.org/10.1186/ar1167
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1186/ar1167