The emerging role of Interleukin 27 in inflammatory arthritis and bone destruction

Abstract

Although the causes of inflammatory arthritis elude us, aberrant cytokine expression has been linked to joint pathology. Consequently, several approaches in the clinic and/or in clinical trials are targeting cytokines, e.g. tumor necrosis factor (TNF), Interleukin 23 (IL-23) and Interleukin 17 (IL-17), with the goal of antagonizing their respective biologic activity through therapeutic neutralizing antibodies. Such, cytokine signaling-dependent molecular networks orchestrate synovial inflammation on multiple levels including differentiation of myeloid cells to osteoclasts, the central cellular players in arthritis-associated pathologic bone resorption. Hence, understanding of the cellular and molecular mechanisms elicited by synovial cytokine networks that dictate recruitment, differentiation and activation of osteoclast precursors and osteoclasts, respectively, is central to shaping novel therapeutic options for inflammatory arthritis patients. In this article we are discussing the complex signaling interactions involved in the regulation of inflammatory arthritis and it's associated bone loss with a focus on Interleukin 27 (IL-27). The present review will discuss the primary bone-degrading cell, the osteoclast, and on how IL-27, directly or indirectly, modulates osteoclast activity in autoimmune-driven inflammatory joint diseases.

Figure 1. The IL-27 and IL-27 receptor

Schematic representation of IL-27 and the IL-27 receptor complex, demonstrating a significant homology with other IL-12 receptor family members. IL-27 shares Ebi3 with IL-35 whilst p28 may signal on its own or form complexes with CLF-1. IL-27 receptor complex shares gp130 with IL-35 and IL-6 receptors. IL-12Rβ2 is shared among IL-12, IL-23, and IL-35 receptors further increasing the possibility of signaling complexes.

Figure 2. Direct and indirect modulation of osteoclast differentiation by IL-27

Schematic representation depicting the molecular events of IL-27 direct inhibition of osteoclast differentiation by downregulation of key osteoclast specific genes RANK, c-fos, NFκB, NFATc1 and TREM-2. Indirect inhibition of osteoclast formation is also achieved, by promoting Th1 cell differentiation and inhibiting the differentiation of osteoclastogenic subset Th17 and the secretion of pro-osteoclastogenic factors RANKL, IL-17 and TNF.