TNF-α and IL-6: The Link between Immune and Bone System

Author(s): Tiantian Wang, Chengqi He*

Journal Name: Current Drug Targets

Volume 21 , Issue 3 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Osteoimmunology is a new subject which focuses on the communication between the immune and the skeletal systems. Both the immune system and bone communicate with each other. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) play important roles in immune responses and bone metabolism. TNF-α and IL-6 enhance macrophage activation and antigen presentation, as well as regulating immunity through different mechanisms.

A variety of groups have reported that TNF-α suppresses osteoblasts activity at some stages of differentiation and stimulates osteoclast proliferation and differentiation. In contrast, IL-6 mediates the actions of osteoblasts and osteoclasts through sophisticated mechanisms, which reflect dual effects. Both TNF-α and IL-6 can mediate the activity of osteocytes. Furthermore, both TNF-α and IL-6 are important pathogenic factors related to immune-mediated bone diseases including rheumatoid arthritis and postmenopausal osteoporosis. This review will discuss the contradictory findings concerning TNF-α and IL-6 in osteoimmunology and their potential for clinical application.

Keywords: TNF-α, IL-6, osteoimmunology, osteoclast, osteoblast, osteocyte.

Arron JR, Choi Y. Bone versus immune system. Nature 2000; 408(6812): 535-6.
[] [PMID: 11117729]
Danks L, Takayanagi H. Immunology and bone. J Biochem 2013; 154(1): 29-39.
[] [PMID: 23750028]
Weiss JM, Renkl AC, Maier CS, et al. Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and dendritic cell migration to lymph nodes. J Exp Med 2001; 194(9): 1219-29.
[] [PMID: 11696588]
Caetano-Lopes J, Canhão H, Fonseca JE. Osteoimmunology--the hidden immune regulation of bone. Autoimmun Rev 2009; 8(3): 250-5.
[] [PMID: 18722561]
Takayanagi H. New developments in osteoimmunology. Nat Rev Rheumatol 2012; 8(11): 684-9.
[] [PMID: 23070645]
Luo G, He Y, Zhao Q, Yu X. Immune Cells Act as Promising Targets for the Treatment of Bone Metastasis. Recent Patents Anticancer Drug Discov 2017; 12(3): 221-33.
[] [PMID: 28595538]
Tang M, Tian L, Luo G, Yu X. Interferon-Gamma-Mediated Osteoimmunology. Front Immunol 2018; 9: 1508.
[] [PMID: 30008722]
Mori G, D’Amelio P, Faccio R, Brunetti G. The Interplay between the bone and the immune system. Clin Dev Immunol 2013; 2013: 720504
[] [PMID: 23935650]
Gallagher JC. Advances in bone biology and new treatments for bone loss. Maturitas 2008; 60(1): 65-9.
[] [PMID: 18555623]
Costa MHG, de Soure AM, Cabral JMS, Ferreira FC, da Silva CL. Hematopoietic niche - exploring biomimetic cues to improve the functionality of hematopoietic stem/progenitor cells. Biotechnol J 2018; 13(2)
[] [PMID: 29178199]
Anthony BA, Link DC. Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol 2014; 35(1): 32-7.
[] [PMID: 24210164]
Garg P, Mazur MM, Buck AC, Wandtke ME, Liu J, Ebraheim NA. Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop Surg 2017; 9(1): 13-9.
[] [PMID: 28276640]
Fu Y, Wang T, Xiu L, et al. Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo. Int Immunopharmacol 2016; 31: 57-65.
[] [PMID: 26706452]
Siracusa F, Alp OS, Maschmeyer P, et al. Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation. Eur J Immunol 2017; 47(11): 1900-5.
[] [PMID: 28815584]
Tokoyoda K, Zehentmeier S, Hegazy AN, et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 2009; 30(5): 721-30.
[] [PMID: 19427242]
Glatman Zaretsky A, Konradt C, Dépis F, et al. T regulatory cells support plasma cell populations in the bone marrow. Cell Rep 2017; 18(8): 1906-16.
[] [PMID: 28228257]
Manko VM. B lymphocyte regulation of proliferation and differentiation of hematopoietic stem cells. Russ J Immunol 1996; 1(1): 9-16.
[PMID: 12687036]
Carlsten M, Baumann BC, Simonsson M, et al. Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia 2010; 24(9): 1607-16.
[] [PMID: 20613786]
Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001; 19(3): 180-92.
[] [PMID: 11359943]
Grey A, Beckley V, Doyle A, et al. Pioglitazone increases bone marrow fat in type 2 diabetes: results from a randomized controlled trial. Eur J Endocrinol 2012; 166(6): 1087-91.
[] [PMID: 22408124]
Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009; 180(1): 32-9.
[] [PMID: 19073651]
Komori T. Requisite roles of Runx2 and Cbfb in skeletal development. J Bone Miner Metab 2003; 21(4): 193-7.
[PMID: 12811622]
Liu ZJ, Zhuge Y, Velazquez OC. Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem 2009; 106(6): 984-91.
[] [PMID: 19229871]
Bar-Shavit Z. The osteoclast: a multinucleated, hematopoietic-origin, bone-resorbing osteoimmune cell. J Cell Biochem 2007; 102(5): 1130-9.
[] [PMID: 17955494]
Quinn JM, Neale S, Fujikawa Y, McGee JO, Athanasou NA. Human osteoclast formation from blood monocytes, peritoneal macrophages, and bone marrow cells. Calcif Tissue Int 1998; 62(6): 527-31.
[] [PMID: 9576981]
Ross FP. M-CSF, c-Fms, and signaling in osteoclasts and their precursors. Ann N Y Acad Sci 2006; 1068: 110-6.
[] [PMID: 16831911]
Sharma SM, Bronisz A, Hu R, et al. MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. J Biol Chem 2007; 282(21): 15921-9.
[] [PMID: 17403683]
Kim K, Kim JH, Lee J, et al. Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J Biol Chem 2005; 280(42): 35209-16.
[] [PMID: 16109714]
Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J. Regulation of Osteoclast Differentiation by Cytokine Networks. Immune Netw 2018; 18(1)e8
[] [PMID: 29503739]
Criscitiello C, Viale G, Gelao L, et al. Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment. Cancer Treat Rev 2015; 41(2): 61-8.
[] [PMID: 25499997]
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.
[] [PMID: 9878548]
Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. 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): 31155-61.
[] [PMID: 10859303]
Lee SE, Woo KM, Kim SY, et al. The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone 2002; 30(1): 71-7.
[] [PMID: 11792567]
Seshasayee D, Wang H, Lee WP, et al. A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response. J Biol Chem 2004; 279(29): 30202-9.
[] [PMID: 15145935]
Fodor S, Jakus Z, Mócsai A. ITAM-based signaling beyond the adaptive immune response. Immunol Lett 2006; 104(1-2): 29-37.
[] [PMID: 16332394]
Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 2009; 231(1): 241-56.
[] [PMID: 19754901]
Hozumi A, Osaki M, Goto H, Sakamoto K, Inokuchi S, Shindo H. Bone marrow adipocytes support dexamethasone-induced osteoclast differentiation. Biochem Biophys Res Commun 2009; 382(4): 780-4.
[] [PMID: 19324007]
Goto H, Osaki M, Fukushima T, et al. Human bone marrow adipocytes support dexamethasone-induced osteoclast differentiation and function through RANKL expression. Biomed Res 2011; 32(1): 37-44.
[] [PMID: 21383509]
Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med 2007; 13(12): 1496-503.
[] [PMID: 18059282]
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136(7): 2348-57.
[PMID: 2419430]
Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006; 203(12): 2673-82.
[] [PMID: 17088434]
Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006; 18(3): 349-56.
[] [PMID: 16616472]
Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994; 12: 635-73.
[] [PMID: 7912089]
Adamopoulos IE, Bowman EP. Immune regulation of bone loss by Th17 cells. Arthritis Res Ther 2008; 10(5): 225.
[] [PMID: 18983698]
Briolay A, Lencel P, Bessueille L, Caverzasio J, Buchet R, Magne D. Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells. Biochem Biophys Res Commun 2013; 430(3): 1072-7.
[] [PMID: 23266365]
Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003; 3(3): 253-7.
[] [PMID: 12658273]
Reiner SL. Development in motion: helper T cells at work. Cell 2007; 129(1): 33-6.
[] [PMID: 17418783]
Pacifici R. T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci 2016; 1364: 11-24.
[] [PMID: 26662934]
Choi Y, Woo KM, Ko SH, et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8(+) T cells. Eur J Immunol 2001; 31(7): 2179-88.
[<2179:AID-IMMU2179>3.0.CO;2-X] [PMID: 11449372]
Terauchi M, Li JY, Bedi B, et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab 2009; 10(3): 229-40.
[] [PMID: 19723499]
Ono T, Okamoto K, Nakashima T, et al. IL-17-producing γδ T cells enhance bone regeneration. Nat Commun 2016; 7: 10928.
[] [PMID: 26965320]
Luo CY, Wang L, Sun C, Li DJ. Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol 2011; 8(1): 50-8.
[] [PMID: 21200384]
Buchwald ZS, Kiesel JR, DiPaolo R, Pagadala MS, Aurora R. Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro. PLoS One 2012; 7(6)e38199
[] [PMID: 22701612]
Horowitz MC, Fretz JA, Lorenzo JA. How B cells influence bone biology in health and disease. Bone 2010; 47(3): 472-9.
[] [PMID: 20601290]
Miyaura C, Onoe Y, Inada M, et al. Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency. Proc Natl Acad Sci USA 1997; 94(17): 9360-5.
[] [PMID: 9256487]
Masuzawa T, Miyaura C, Onoe Y, et al. Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow. J Clin Invest 1994; 94(3): 1090-7.
[] [PMID: 8083350]
Erlandsson MC, Jonsson CA, Islander U, Ohlsson C, Carlsten H. Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice. Immunology 2003; 108(3): 346-51.
[] [PMID: 12603601]
McGinty T, Mirmonsef P, Mallon PW, Landay AL. Does systemic inflammation and immune activation contribute to fracture risk in HIV? Curr Opin HIV AIDS 2016; 11(3): 253-60.
[] [PMID: 27008474]
Kozuka Y, Ozaki Y, Ukai T, Kaneko T, Hara Y. B cells play an important role in lipopolysaccharide-induced bone resorption. Calcif Tissue Int 2006; 78(3): 125-32.
[] [PMID: 16467977]
Choi Y, Kim JJ. B cells activated in the presence of Th1 cytokines inhibit osteoclastogenesis. Exp Mol Med 2003; 35(5): 385-92.
[] [PMID: 14646592]
Weitzmann MN, Cenci S, Haug J, Brown C, DiPersio J, Pacifici R. B lymphocytes inhibit human osteoclastogenesis by secretion of TGFbeta. J Cell Biochem 2000; 78(2): 318-24.
[<318::AID-JCB13>3.0.CO;2-N] [PMID: 10842325]
Lanier LL. NK cell recognition. Annu Rev Immunol 2005; 23: 225-74.
[] [PMID: 15771571]
Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 2001; 97(10): 3146-51.
[] [PMID: 11342442]
Wilder JA, Koh CY, Yuan D. The role of NK cells during in vivo antigen-specific antibody responses. J Immunol 1996; 156(1): 146-52.
[PMID: 8598455]
Martín-Fontecha A, Thomsen LL, Brett S, et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 2004; 5(12): 1260-5.
[] [PMID: 15531883]
Hu M, Bassett JH, Danks L, et al. Activated invariant NKT cells regulate osteoclast development and function. J Immunol 2011; 186(5): 2910-7.
[] [PMID: 21278350]
Söderström K, Stein E, Colmenero P, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci USA 2010; 107(29): 13028-33.
[] [PMID: 20615964]
Feng S, Madsen SH, Viller NN, et al. Interleukin-15-activated natural killer cells kill autologous osteoclasts via LFA-1, DNAM-1 and TRAIL, and inhibit osteoclast-mediated bone erosion in vitro. Immunology 2015; 145(3): 367-79.
[] [PMID: 25684021]
McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000; 95(11): 3489-97.
[PMID: 10828034]
Page G, Miossec P. RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes. Arthritis Rheum 2005; 52(8): 2307-12.
[] [PMID: 16052586]
Page G, Lebecque S, Miossec P. Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. J Immunol 2002; 168(10): 5333-41.
[] [PMID: 11994492]
Rivollier A, Mazzorana M, Tebib J, et al. Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment. Blood 2004; 104(13): 4029-37.
[] [PMID: 15308576]
Jacobs L, Nawrot TS, de Geus B, et al. Subclinical responses in healthy cyclists briefly exposed to traffic-related air pollution: an intervention study. Environ Health 2010; 9: 64.
[] [PMID: 20973949]
Poubelle PE, Chakravarti A, Fernandes MJ, Doiron K, Marceau AA. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther 2007; 9(2): R25.
[] [PMID: 17341304]
Chakravarti A, Raquil MA, Tessier P, Poubelle PE. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood 2009; 114(8): 1633-44.
[] [PMID: 19546479]
Okamoto K, Nakashima T, Shinohara M, et al. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiol Rev 2017; 97(4): 1295-349.
[] [PMID: 28814613]
Yu VW, Saez B, Cook C, et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med 2015; 212(5): 759-74.
[] [PMID: 25918341]
Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood 2010; 116(2): 210-7.
[] [PMID: 20304810]
Grassi F, Manferdini C, Cattini L, et al. T cell suppression by osteoclasts in vitro. J Cell Physiol 2011; 226(4): 982-90.
[] [PMID: 20857429]
Pappalardo A, Thompson K. Novel immunostimulatory effects of osteoclasts and macrophages on human γδ T cells. Bone 2015; 71: 180-8.
[] [PMID: 25445456]
Miyamoto K, Yoshida S, Kawasumi M, et al. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J Exp Med 2011; 208(11): 2175-81.
[] [PMID: 22006978]
Sato M, Asada N, Kawano Y, et al. Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab 2013; 18(5): 749-58.
[] [PMID: 24140021]
Cain CJ, Rueda R, McLelland B, Collette NM, Loots GG, Manilay JO. Absence of sclerostin adversely affects B-cell survival. J Bone Miner Res 2012; 27(7): 1451-61.
[] [PMID: 22434688]
Iseme RA, Mcevoy M, Kelly B, Agnew L, Walker FR, Attia J. Is osteoporosis an autoimmune mediated disorder? Bone Rep 2017; 7: 121-31.
[] [PMID: 29124082]
Ginaldi L, De Martinis M. Osteoimmunology and Beyond. Curr Med Chem 2016; 23(33): 3754-74.
[] [PMID: 27604089]
Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008; 118(11): 3537-45.
[] [PMID: 18982160]
Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol 2008; 61(5): 577-87.
[] [PMID: 18441154]
Ginaldi L, De Martinis M, Ciccarelli F, et al. Increased levels of interleukin 31 (IL-31) in osteoporosis. BMC Immunol 2015; 16: 60.
[] [PMID: 26449657]
Ginaldi L, De Martinis M, Saitta S, et al. Interleukin-33 serum levels in postmenopausal women with osteoporosis. Sci Rep 2019; 9(1): 3786.
[] [PMID: 30846811]
Wang T, He C, Yu X. Pro-inflammatory cytokines: new potential therapeutic targets for obesity-related bone disorders. Curr Drug Targets 2017; 18(14): 1664-75.
[] [PMID: 28056748]
Algood HM, Chan J, Flynn JL. Chemokines and tuberculosis. Cytokine Growth Factor Rev 2003; 14(6): 467-77.
[] [PMID: 14563349]
Harris J, Hope JC, Keane J. Tumor necrosis factor blockers influence macrophage responses to Mycobacterium tuberculosis. J Infect Dis 2008; 198(12): 1842-50.
[] [PMID: 18954258]
Bekker LG, Moreira AL, Bergtold A, Freeman S, Ryffel B, Kaplan G. Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent. Infect Immun 2000; 68(12): 6954-61.
[] [PMID: 11083819]
Mootoo A, Stylianou E, Arias MA, Reljic R. TNF-alpha in tuberculosis: a cytokine with a split personality. Inflamm Allergy Drug Targets 2009; 8(1): 53-62.
[] [PMID: 19275693]
Abbas S, Zhang YH, Clohisy JC, Abu-Amer Y. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor. Cytokine 2003; 22(1-2): 33-41.
[] [PMID: 12946103]
Kaneki H, Guo R, Chen D, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 2006; 281(7): 4326-33.
[] [PMID: 16373342]
Gilbert L, He X, Farmer P, et al. Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 2000; 141(11): 3956-64.
[] [PMID: 11089525]
Zhang H, Hilton MJ, Anolik JH, et al. NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB. J Clin Invest 2014; 124(7): 3200-14.
[] [PMID: 24892805]
Mukai T, Otsuka F, Otani H, et al. TNF-alpha inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling. Biochem Biophys Res Commun 2007; 356(4): 1004-10.
[] [PMID: 17397798]
Yamazaki M, Fukushima H, Shin M, et al. Tumor necrosis factor alpha represses bone morphogenetic protein (BMP) signaling by interfering with the DNA binding of Smads through the activation of NF-kappaB. J Biol Chem 2009; 284(51): 35987-95.
[] [PMID: 19854828]
Hess K, Ushmorov A, Fiedler J, Brenner RE, Wirth T. TNFalpha promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-kappaB signaling pathway. Bone 2009; 45(2): 367-76.
[] [PMID: 19414075]
Huang H, Zhao N, Xu X, et al. Dose-specific effects of tumor necrosis factor alpha on osteogenic differentiation of mesenchymal stem cells. Cell Prolif 2011; 44(5): 420-7.
[] [PMID: 21951285]
Glass GE, Chan JK, Freidin A, Feldmann M, Horwood NJ, Nanchahal J. TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proc Natl Acad Sci USA 2011; 108(4): 1585-90.
[] [PMID: 21209334]
Cho HH, Shin KK, Kim YJ, et al. NF-kappaB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression. J Cell Physiol 2010; 223(1): 168-77.
[PMID: 20049872]
Guo J, Jin J, Cooper LF. Dissection of sets of genes that control the character of wnt5a-deficient mouse calvarial cells. Bone 2008; 43(5): 961-71.
[] [PMID: 18656562]
Osta B, Benedetti G, Miossec P. Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Front Immunol 2014; 5: 48.
[] [PMID: 24592264]
Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007; 13(2): 156-63.
[] [PMID: 17237793]
Ross FP, Teitelbaum SL. alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev 2005; 208: 88-105.
[] [PMID: 16313343]
Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 2002; 20: 795-823.
[] [PMID: 11861618]
Hodge JM, Collier FM, Pavlos NJ, Kirkland MA, Nicholson GC. M-CSF potently augments RANKL-induced resorption activation in mature human osteoclasts. PLoS One 2011; 6(6)e21462
[] [PMID: 21738673]
Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem 2001; 276(1): 563-8.
[] [PMID: 11032840]
Li P, Schwarz EM, O’Keefe RJ, et al. Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum 2004; 50(1): 265-76.
[] [PMID: 14730625]
Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000; 106(12): 1481-8.
[] [PMID: 11120755]
Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 2000; 275(7): 4858-64.
[] [PMID: 10671521]
Moon SJ, Ahn IE, Jung H, et al. Temporal differential effects of proinflammatory cytokines on osteoclastogenesis. Int J Mol Med 2013; 31(4): 769-77.
[] [PMID: 23403591]
Takayanagi H, Kim S, Taniguchi T. Signaling crosstalk between RANKL and interferons in osteoclast differentiation. Arthritis Res 2002; 4(Suppl. 3): S227-32.
[] [PMID: 12110142]
Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem 1998; 273(43): 28355-9.
[] [PMID: 9774460]
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): 600-5.
[] [PMID: 11117749]
Yao Z, Lei W, Duan R, Li Y, Luo L, Boyce BF. RANKL cytokine enhances TNF-induced osteoclastogenesis independently of TNF receptor associated factor (TRAF) 6 by degrading TRAF3 in osteoclast precursors. J Biol Chem 2017; 292(24): 10169-79.
[] [PMID: 28438834]
Kim N, Kadono Y, Takami M, et al. Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Exp Med 2005; 202(5): 589-95.
[] [PMID: 16147974]
Yao Z, Li P, Zhang Q, et al. Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem 2006; 281(17): 11846-55.
[] [PMID: 16461346]
Kaplan DL, Eielson CM, Horowitz MC, Insogna KL, Weir EC. Tumor necrosis factor-alpha induces transcription of the colony-stimulating factor-1 gene in murine osteoblasts. J Cell Physiol 1996; 168(1): 199-208.
[<199:: AID-JCP24>3.0.CO;2-1] [PMID: 8647916]
Cenci S, Weitzmann MN, Roggia C, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 2000; 106(10): 1229-37.
[] [PMID: 11086024]
Yarilina A, Xu K, Chen J, Ivashkiv LB. TNF activates calcium-nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages. Proc Natl Acad Sci USA 2011; 108(4): 1573-8.
[] [PMID: 21220349]
Kitaura H, Nagata N, Fujimura Y, Hotokezaka H, Yoshida N, Nakayama K. Effect of IL-12 on TNF-α-mediated osteoclast formation in bone marrow cells: apoptosis mediated by Fas/Fas ligand interaction. J Immunol 2002; 169(9): 4732-8.
[] [PMID: 12391181]
Morita Y, Kitaura H, Yoshimatsu M, et al. IL-18 inhibits TNF-alpha-induced osteoclastogenesis possibly via a T cell-independent mechanism in synergy with IL-12 in vivo. Calcif Tissue Int 2010; 86(3): 242-8.
[] [PMID: 20111957]
Kohara H, Kitaura H, Fujimura Y, et al. IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions. Immunol Lett 2011; 137(1-2): 53-61.
[] [PMID: 21338623]
Wang T, Yu X, He C. Pro-inflammatory cytokines: cellular and molecular drug targets for glucocorticoid-induced-osteoporosis via osteocyte. Curr Drug Targets 2018.
[] [PMID: 29618305]
Cheung WY, Simmons CA, You L. Osteocyte apoptosis regulates osteoclast precursor adhesion via osteocytic IL-6 secretion and endothelial ICAM-1 expression. Bone 2012; 50(1): 104-10.
[] [PMID: 21986000]
Cheung WY, Liu C, Tonelli-Zasarsky RM, Simmons CA, You L. Osteocyte apoptosis is mechanically regulated and induces angiogenesis in vitro. J Orthop Res 2011; 29(4): 523-30.
[] [PMID: 21337392]
Kohno S, Kaku M, Tsutsui K, et al. Expression of vascular endothelial growth factor and the effects on bone remodeling during experimental tooth movement. J Dent Res 2003; 82(3): 177-82.
[] [PMID: 12598545]
Bakker AD, Silva VC, Krishnan R, et al. Tumor necrosis factor alpha and interleukin-1beta modulate calcium and nitric oxide signaling in mechanically stimulated osteocytes. Arthritis Rheum 2009; 60(11): 3336-45.
[] [PMID: 19877030]
Collin-Osdoby P, Rothe L, Bekker S, Anderson F, Osdoby P. Decreased nitric oxide levels stimulate osteoclastogenesis and bone resorption both in vitro and in vivo on the chick chorioallantoic membrane in association with neoangiogenesis. J Bone Miner Res 2000; 15(3): 474-88.
[] [PMID: 10750562]
Kitaura H, Fujimura Y, Yoshimatsu M, et al. IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-α-mediated osteoclastogenesis of bone marrow cells. Calcif Tissue Int 2011; 89(1): 65-73.
[] [PMID: 21611811]
Byun CH, Koh JM, Kim DK, Park SI, Lee KU, Kim GS. Alpha-lipoic acid inhibits TNF-alpha-induced apoptosis in human bone marrow stromal cells. J Bone Miner Res 2005; 20(7): 1125-35.
[] [PMID: 15940365]
Ito N, Wijenayaka AR, Prideaux M, et al. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol 2015; 399: 208-18.
[] [PMID: 25458698]
Dupond JL, Mahammedi H, Prié D, et al. Oncogenic osteomalacia: diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case. Bone 2005; 36(3): 375-8.
[] [PMID: 15777669]
Reeve J, Arlot M, Wootton R, et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. J Clin Endocrinol Metab 1988; 66(6): 1124-31.
[] [PMID: 3372678]
Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood 1995; 86(4): 1243-54.
[PMID: 7632928]
Fonseca JE, Santos MJ, Canhão H, Choy E. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev 2009; 8(7): 538-42.
[] [PMID: 19189867]
Kaneshiro S, Ebina K, Shi K, et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J Bone Miner Metab 2014; 32(4): 378-92.
[] [PMID: 24122251]
Peruzzi B, Cappariello A, Del Fattore A, Rucci N, De Benedetti F, Teti A. c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nat Commun 2012; 3: 630.
[] [PMID: 22252554]
Franchimont N, Gangji V, Durant D, Canalis E. Interleukin-6 with its soluble receptor enhances the expression of insulin-like growth factor-I in osteoblasts. Endocrinology 1997; 138(12): 5248-55.
[] [PMID: 9389508]
Yeh LC, Zavala MC, Lee JC. Osteogenic protein-1 and interleukin-6 with its soluble receptor synergistically stimulate rat osteoblastic cell differentiation. J Cell Physiol 2002; 190(3): 322-31.
[] [PMID: 11857448]
Guillén C, de Gortázar AR, Esbrit P. The interleukin-6/soluble interleukin-6 receptor system induces parathyroid hormone-related protein in human osteoblastic cells. Calcif Tissue Int 2004; 75(2): 153-9.
[] [PMID: 15129368]
Malaval L, Aubin JE. Biphasic effects of leukemia inhibitory factor on osteoblastic differentiation. J Cell Biochem Suppl 2001; (Suppl. 36)63-70.
[] [PMID: 11455571]
Malaval L, Liu F, Vernallis AB, Aubin JE. GP130/OSMR is the only LIF/IL-6 family receptor complex to promote osteoblast differentiation of calvaria progenitors. J Cell Physiol 2005; 204(2): 585-93.
[] [PMID: 15751050]
Falconi D, Aubin JE. LIF inhibits osteoblast differentiation at least in part by regulation of HAS2 and its product hyaluronan. J Bone Miner Res 2007; 22(8): 1289-300.
[] [PMID: 17451373]
Palmqvist P, Persson E, Conaway HH, Lerner UH. IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 2002; 169(6): 3353-62.
[] [PMID: 12218157]
O’Brien CA, Lin SC, Bellido T, Manolagas SC. Expression levels of gp130 in bone marrow stromal cells determine the magnitude of osteoclastogenic signals generated by IL-6-type cytokines. J Cell Biochem 2000; 79(4): 532-41.
[<532:AID-JCB20>3.0.CO;2-U] [PMID: 10996844]
Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003; 32(1): 1-7.
[] [PMID: 12584029]
Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441(7090): 235-8.
[] [PMID: 16648838]
Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 2006; 54(1): 158-68.
[] [PMID: 16385511]
Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S. Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem 2008; 283(17): 11535-40.
[] [PMID: 18296709]
Duplomb L, Baud’huin M, Charrier C, et al. Interleukin-6 inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology 2008; 149(7): 3688-97.
[] [PMID: 18403479]
Bakker AD, Kulkarni RN, Klein-Nulend J, Lems WF. IL-6 alters osteocyte signaling toward osteoblasts but not osteoclasts. J Dent Res 2014; 93(4): 394-9.
[] [PMID: 24492932]
Chen W, Ma Y, Ye H, et al. ERK1/2 is involved in cyclic compressive force-induced IL-6 secretion in MLO-Y4 cells. Biochem Biophys Res Commun 2010; 401(3): 339-43.
[] [PMID: 20849821]
Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17(10): 1231-4.
[] [PMID: 21909105]
Juffer P, Jaspers RT, Lips P, Bakker AD, Klein-Nulend J. Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes. Am J Physiol Endocrinol Metab 2012; 302(4): E389-95.
[] [PMID: 22114022]
Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 1998; 152(4): 943-51.
[PMID: 9546355]
Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000; 43(2): 250-8.
[<250::AID-ANR3>3.0.CO;2-P] [PMID: 10693863]
Walsh NC, Reinwald S, Manning CA, et al. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res 2009; 24(9): 1572-85.
[] [PMID: 19338457]
Walsh NC, Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev 2010; 233(1): 301-12.
[] [PMID: 20193007]
Angelotti F, Parma A, Cafaro G, Capecchi R, Alunno A, Puxeddu I. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 2017; 35(3): 368-78.
[PMID: 28631608]
Shim JH, Stavre Z, Gravallese EM. Bone loss in rheumatoid arthritis: basic mechanisms and clinical implications. Calcif Tissue Int 2018; 102(5): 533-46.
[] [PMID: 29204672]
Hou Y, Lin H, Zhu L, et al. The inhibitory effect of IFN-γ on protease HTRA1 expression in rheumatoid arthritis. J Immunol 2014; 193(1): 130-8.
[] [PMID: 24907345]
Frank S, Peters MA, Wehmeyer C, et al. Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-κB. Ann Rheum Dis 2013; 72(11): 1874-81.
[] [PMID: 23417988]
Komine M, Kukita A, Kukita T, Ogata Y, Hotokebuchi T, Kohashi O. Tumor necrosis factor-alpha cooperates with receptor activator of nuclear factor kappaB ligand in generation of osteoclasts in stromal cell-depleted rat bone marrow cell culture. Bone 2001; 28(5): 474-83.
[] [PMID: 11344046]
Kotake S, Udagawa N, Hakoda M, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001; 44(5): 1003-12.
[<1003::AID-ANR179>3.0.CO;2-#] [PMID: 11352231]
Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010; 233(1): 233-55.
[] [PMID: 20193003]
Toussirot É, Mourot L, Dehecq B, Wendling D, Grandclément É, Dumoulin G. CBT-506. TNFα blockade for inflammatory rheumatic diseases is associated with a significant gain in android fat mass and has varying effects on adipokines: a 2-year prospective study. Eur J Nutr 2014; 53(3): 951-61.
[] [PMID: 24173963]
Marotte H, Pallot-Prades B, Grange L, Gaudin P, Alexandre C, Miossec P. A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab. Arthritis Res Ther 2007; 9(3): R61.
[] [PMID: 17597527]
Saidenberg-Kermanac’h N, Corrado A, Lemeiter D, deVernejoul MC, Boissier MC, Cohen-Solal ME. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone 2004; 35(5): 1200-7.
[] [PMID: 15542046]
Kishimoto T. Interleukin-6: from basic science to medicine--40 years in immunology. Annu Rev Immunol 2005; 23: 1-21.
[] [PMID: 15771564]
Kotake S, Sato K, Kim KJ, et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996; 11(1): 88-95.
[] [PMID: 8770701]
Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford) 2010; 49(1): 15-24.
[] [PMID: 19854855]
Navarro-Millán I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012; 34(4): 788-802.e3.
[] [PMID: 22444783]
Shetty A, Hanson R, Korsten P, et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther 2014; 8: 349-64.
[PMID: 24729685]
Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handb Exp Pharmacol 2008; (181): 151-60.
[] [PMID: 18071945]
Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum 2010; 62(1): 33-43.
[] [PMID: 20039425]
Kume K, Amano K, Yamada S, et al. The effect of tocilizumab on bone mineral density in patients with methotrexate-resistant active rheumatoid arthritis. Rheumatology (Oxford) 2014; 53(5): 900-3.
[] [PMID: 24441151]
Pacifici R. Estrogen deficiency, T cells and bone loss. Cell Immunol 2008; 252(1-2): 68-80.
[] [PMID: 17888417]
Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 1992; 257(5066): 88-91.
[] [PMID: 1621100]
Roggia C, Gao Y, Cenci S, et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci USA 2001; 98(24): 13960-5.
[] [PMID: 11717453]
Ammann P, Rizzoli R, Bonjour JP, et al. Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest 1997; 99(7): 1699-703.
[] [PMID: 9120014]
Girasole G, Passeri G, Jilka RL, Manolagas SC. Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest 1994; 93(4): 1516-24.
[] [PMID: 8163655]
D’Amelio P, Grimaldi A, Di Bella S, et al. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone 2008; 43(1): 92-100.
[] [PMID: 18407820]
Pacifici R, Brown C, Puscheck E, et al. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA 1991; 88(12): 5134-8.
[] [PMID: 2052592]
Pfeilschifter J, Köditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev 2002; 23(1): 90-119.
[] [PMID: 11844745]
Weitzmann MN, Pacifici R. Estrogen regulation of immune cell bone interactions. Ann N Y Acad Sci 2006; 1068: 256-74.
[] [PMID: 16831927]
Pino AM, Ríos S, Astudillo P, et al. Concentration of adipogenic and proinflammatory cytokines in the bone marrow supernatant fluid of osteoporotic women. J Bone Miner Res 2010; 25(3): 492-8.
[] [PMID: 19653807]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 21 February, 2020
Page: [213 - 227]
Pages: 15
DOI: 10.2174/1389450120666190821161259
Price: $65

Article Metrics

PDF: 72
HTML: 19