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

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

^* Both are first authors with equal contributions to this study.

Publication History

Article published online:
24 September 2020

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