IL-6-induced response of human osteoblasts from patients with rheumatoid arthritis after inhibition of the signaling pathway

Abstract

AbstractInterleukin (IL-) 6 is a critical factor in inflammatory processes of rheumatoid arthritis (RA). This is of high interest as the progression of RA may lead to the implantation of joint endoprostheses, which is associated with a pro-inflammatory increase in IL-6 in the periprosthetic tissue. Biological agents such as sarilumab have been developed to inhibit IL-6-mediated signaling. However, IL-6 signaling blockade should consider the inhibition of inflammatory processes and the regenerative functions of IL-6. This in vitro study investigated whether inhibiting IL-6 receptors can affect the differentiation of osteoblasts isolated from patients with RA. Since wear particles can be generated at the articular surfaces of endoprostheses leading to osteolysis and implant loosening, the potential of sarilumab to inhibit wear particle-induced pro-inflammatory processes should be investigated. Both in monocultures and indirect co-cultures with osteoclast-like cells (OLCs), human osteoblasts were stimulated with 50 ng/mL each of IL-6 + sIL-6R and in combination with sarilumab (250 nM) to characterize cell viability and osteogenic differentiation capacity. Furthermore, the influence of IL-6 + sIL-6R or sarilumab on viability, differentiation, and inflammation was evaluated in osteoblasts exposed to particles. Stimulation with IL-6 + sIL-6R and sarilumab did not affect cell viability. Except for the significant induction of RUNX2 mRNA by IL-6 + sIL-6R and a significant reduction with sarilumab, no effects on cell differentiation and mineralization could be detected. Furthermore, the different stimulations did not affect the osteogenic and osteoclastic differentiation of co-cultured cells. Compared to the osteoblastic monocultures, a decreased release of IL-8 was triggered in the co-culture. Among these, treatment with sarilumab alone resulted in the greatest reduction of IL-8. The co-culture also showed clearly increased OPN concentrations than the respective monocultures, with OPN secretion apparently triggered by the OLCs. Particle exposure demonstrated decreased osteogenic differentiation using different treatment strategies. However, sarilumab administration caused a trend toward a decrease in IL-8 production after stimulation with IL-6 + sIL-6R. The blockade of IL-6 and its pathway have no significant effect on the osteogenic and osteoclastic differentiation of bone cells derived from patients with RA. Nonetheless, observed effects on the reduced IL-8 secretion need further investigation.