IL-17 regulates expression of cytokines in human osteoblasts rather than bone-specific genes

Andreas Drynda; Susanne Drynda; Christoph H. Lohmann; Jessica Bertrand; Jörn Kekow

doi:10.1055/a-1177-5073

Osteologie, Table of Contents

Osteologie 2021; 30(01): 49-56
DOI: 10.1055/a-1177-5073

Original Article

IL-17 regulates expression of cytokines in human osteoblasts rather than bone-specific genes

Einfluss von IL-17 auf die Expression pro-inflammatorischer Zytokine in primären humanen Osteoblasten

Authors

Andreas Drynda^*

¹Department of Orthopaedic Surgery, Otto-von-Guericke University, Magdeburg, Germany
Susanne Drynda^*

²Clinic for Rheumatology, Otto-von-Guericke University, Magdeburg, Germany
Christoph H. Lohmann

¹Department of Orthopaedic Surgery, Otto-von-Guericke University, Magdeburg, Germany
Jessica Bertrand

¹Department of Orthopaedic Surgery, Otto-von-Guericke University, Magdeburg, Germany
Jörn Kekow

³Immunologisches Zentrum Vogelsang-Gommern GmbH Vogelsang-Gommern, Germany

Abstract

Objective The cytokine IL-17 plays a crucial role in the development and promoting of inflammatory rheumatic diseases, such as psoriasis arthritis and ankylosing spondylitis. The influence of IL-17 on the osteoblast differentiation from mesenchymal stem cells has already been well studied. However, the effect of IL-17 on mature osteoblasts is not yet fully understood.

Methods In this study, the influence of IL-17 on the expression of osteogenic markers and pro-inflammatory cytokines was analyzed on mRNA and protein level in an osteoblast cell culture model.

Results Our data indicate that IL-17 alone has no significant influence on the expression of osteoblast-specific genes. However, a significant upregulation of pro-inflammatory cytokines at the transcriptional level by IL-17 was observed in primary osteoblasts. This effect on the regulation of pro-inflammatory cytokines was abolished completely by administration of a therapeutic anti-IL-17 antibody. Co-stimulation with TNF-α and IL-17 led to an upregulation of pro-inflammatory cytokines, which significantly exceeded the additive effect of both cytokines. In this co-stimulation, the anti-IL-17 antibody could not completely reverse the IL-17 effect. The same IL-17 and TNF-α effect was observed in osteoblast-like cells (MG63), whereas IL-17 alone did not induce the expression of pro-inflammatory cytokines.

Conclusion The upregulation of the pro-inflammatory cytokines IL-1, IL-6, and IL-8 in primary osteoblasts by IL-17 indicates an indirect regulatory effect on osteoclastogenesis and activation of bone resorption. The therapeutic IL-17 antibody reduced the IL-17 induced release of pro-inflammatory cytokines by osteoblasts and this, in turn, could also reduce the effect on osteoclast differentiation and bone resorption. Our study underlines the important role of osteoblasts as major players in the osteoimmunologic network.

Zusammenfassung

Zielsetzung Das Zytokin IL-17 spielt eine zentrale Rolle in der Entwicklung und im Verlauf entzündlicher Autoimmunerkrankungen wie der Psoriasisarthritis und der ankylosierenden Spondylitis. Der Einfluss von IL-17 auf die Ausdifferenzierung von Osteoblasten aus mesenchymalen Stammzellen in vitro ist gut untersucht, jedoch ist über den Einfluss von IL-17 auf reife Osteoblasten bisher weniger bekannt.

Methoden In dieser Studie wurde der Einfluss von IL-17 auf die Expression von osteogenen Markern und pro-inflammatorischen Zytokinen auf mRNA- und Proteinebene in einem In-vitro-Zellkulturmodell untersucht.

Ergebnisse Unsere Daten zeigen, dass IL-17 allein keinen signifikanten Einfluss auf die Expression Osteoblasten-spezifischer Gene hat. Im Gegensatz dazu wurde eine signifikante Hochregulierung pro-inflammatorischer Zytokine auf der transkriptionalen Ebene in primären Osteoblasten beobachtet. Dieser Effekt konnte komplett durch die Gabe eines therapeutischen anti-IL-17-Antikörpers aufgehoben werden. Die Ko-Stimulation mit IL-17 und TNF-α führte zu einer signifikant stärkeren Hochregulierung der pro-inflammatorischen Zytokine, wobei der Effekt beider Zytokine signifikant überschritten wurde. Bei dieser Ko-Stimulation wurde keine komplette Aufhebung des IL-17-Effekts durch den anti-IL-17-Antikörper beobachtet. Der gleiche Effekt wurde in Osteoblasten-ähnlichen Zellen (MG63) beobachtet, wohingegen IL-17 alleine zu keiner Expression von pro-inflammatorischen Zytokinen führte.

Schlussfolgerungen Durch die Hochregulierung der pro-inflammatorischen Zytokine IL-1, IL-6 und IL-8 in primären Osteoblasten durch IL-17 kann ein indirekter regulatorischer Effekt auf die Osteoklastogenese und die Aktivierung der Knochenresorption ausgelöst werden. Der therapeutische IL-17-Antikörper reduziert die durch IL-17 induzierte Freisetzung pro-inflammatorischer Zytokine durch Osteoblasten, wodurch ebenfalls die Osteoklastendifferenzierung und damit die Knochenresorption vermindert werden kann. Die Arbeit unterstreicht die Bedeutung der Osteoblasten als Schlüsselzellen im osteoimmunologischen Netzwerk.

Key words

IL-17 - secukinumab - osteoblast - bone metabolism - pro-inflammatory cytokines - psoriasis arthritis - ankylosing spondylitis

Schlüsselwörter

IL-17 - Secukinumab - Osteoblast - Knochenmetabolismus - proinflammatorische Zytokine - Psoriasisarthritis - Ankylosierende Spondylitis

Full Text

References

References
1 Amarasekara DS, Yun H, Kim S. et al. Regulation of osteoclast differentiation by cytokine networks. Immune Netw 2018; 18: e8 .
2 Boutet M-A, Nerviani A, Pitzalis C. IL-36, IL-37, and IL-38 cytokines in skin and joint inflammation: a comprehensive review of their therapeutic potential. Int J Mol Sci 2019; 20
3 Kragstrup TW, Andersen T, Heftdal LD. et al. The IL-20 cytokine family in rheumatoid arthritis and spondyloarthritis. Front Immunol 2018; 9: 2226 .
4 Dayer J-M. From supernatants to cytokines: a personal view on the early history of IL-1, IL-1Ra, TNF and its inhibitor in rheumatology. Arthritis Res Ther 2018; 20: 101 .
5 Adamopoulos IE, Suzuki E, Chao C-C. et al. IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis. Ann Rheum Dis 2015; 74: 1284-1292 .
6 Marchesoni A, Caporali R, Lubrano E. Clinical implications of peripheral new bone formation in psoriatic arthritis: a literature-based review. Clin Exp Rheumatol 2019; 37: 310-317
7 Okamoto K. Regulation of bone by IL-17-producing T cells. Nihon Rinsho Meneki Gakkai Kaishi 2017; 40: 361-366 .
8 Le Goff B, Bouvard B, Lequerre T. et al. Implication of IL-17 in bone loss and structural damage in inflammatory rheumatic diseases. Mediators Inflamm 2019; 2019: 8659302 .
9 Croes M, Öner FC, van Neerven D. et al. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone 2016; 84: 262-270 .
10 Li J-Y, Yu M, Tyagi AM. et al. IL-17 receptor signaling in osteoblasts/osteocytes mediates PTH-induced bone loss and enhances osteocytic RANKL production. J Bone Miner Res 2019; 34: 349-360 .
11 Hawkes JE, Yan BY, Chan TC. et al. Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis. J Immunol 2018; 201: 1605-1613 .
12 Kim Y-G, Park J-W, Lee J-M. et al. IL-17 inhibits osteoblast differentiation and bone regeneration in rat. Arch Oral Biol 2014; 59: 897-905 .
13 Tyagi AM, Mansoori MN, Srivastava K. et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-α antibodies. J Bone Miner Res 2014; 29: 1981-1992 .
14 Huang H, Kim HJ, Chang E-J. et al. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ 2009; 16: 1332-1343 .
15 Croes M, Oner FC, Kruyt MC. et al. Proinflammatory mediators enhance the osteogenesis of human mesenchymal stem cells after lineage commitment. PLoS One 2015; 10: e0132781 .
16 Pathak JL, Bravenboer N, Verschueren P. et al. Inflammatory factors in the circulation of patients with active rheumatoid arthritis stimulate osteoclastogenesis via endogenous cytokine production by osteoblasts. Osteoporos Int 2014; 25: 2453-2463 .
17 Taylor SEB, Shah M, Orriss IR. Generation of rodent and human osteoblasts. Bonekey Rep 2014; 3: 585 .
18 Billiau A, Edy VG, Heremans H. et al. Human interferon: mass production in a newly established cell line, MG-63. Antimicrob Agents Chemother 1977; 12: 11-15 .
19 Olivares-Navarrete R, Hyzy SL, Berg ME. et al. Osteoblast lineage cells can discriminate microscale topographic features on titanium-aluminum-vanadium surfaces. Ann Biomed Eng 2014; 42: 2551-2561 .
20 Drynda A, Drynda S, Kekow J. et al. Differential effect of cobalt and chromium ions as well as CoCr particles on the expression of osteogenic markers and osteoblast function. Int J Mol Sci 2018; 19
21 Sritharan S, Kannan TP, Norazmi MN. et al. The synergistic effects of IL-6/IL-17A promote osteogenic differentiation by improving OPG/RANKL ratio and adhesion of MC3T3-E1 cells on hydroxyapatite. J Craniomaxillofac Surg 2018; 46: 1361-1367 .
22 Sebastian A-A, Kannan T-P, Norazmi M-N. et al. Interleukin-17A promotes osteogenic differentiation by increasing OPG/RANKL ratio in stem cells from human exfoliated deciduous teeth (SHED). J Tissue Eng Regen Med 2018; 12: 1856-1866 .
23 Honorati MC, Cattini L, Facchini A. Possible prognostic role of IL-17R in osteosarcoma. J Cancer Res Clin Oncol 2007; 133: 1017-1021 .
24 Zhang J-R, Pang D-D, Tong Q. et al. Different modulatory effects of IL-17, IL-22, and IL-23 on osteoblast differentiation. Mediators Inflamm 2017; 2017: 5950395 .
25 Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 2009; 5: 667-676 .
26 Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol 2019; 19: 626-642 .
27 Arron JR, Choi Y. Bone versus immune system. Nature 2000; 408: 535-536 .
28 Kumar G, Roger P-M. From crosstalk between immune and bone cells to bone erosion in infection. Int J Mol Sci 2019 20.
29 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: 2673-2682 .
30 Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 2012; 11: 763-776 .
31 Jo S, Wang SE, Lee YL. et al. IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis. Arthritis Res Ther 2018; 20: 115 .
32 Shim J-H, Stavre Z, Gravallese EM. Bone loss in rheumatoid arthritis: basic mechanisms and clinical implications. Calcif Tissue Int 2018; 102: 533-546 .
33 Chabaud M, Durand JM, Buchs N. et al. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999; 42: 963-970 .
34 Koshy PJ, Henderson N, Logan C. et al. Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Ann Rheum Dis 2002; 61: 704-713 .
35 Honorati MC, Bovara M, Cattini L. et al. Contribution of interleukin 17 to human cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthritis Cartilage 2002; 10: 799-807