Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors

Abstract

IntroductionThe interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.MethodsHuman CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-κB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.ResultsIL-17A upregulates the receptor activator for NF-κB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.ConclusionsCollectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases.

Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics

“…Th17 cells potently induce osteoclastogenesis by secreting IL-17A, RANKL, TNF, IL-1, and IL-6, along with low levels of IFNγ (48)(49)(50). IL-17A stimulates the release of RANKL by all osteoblastic cells including osteocytes (42,51) and increases the osteoclastogenic activity of RANKL by upregulating RANK (52).…”

Inflammatory osteolysis: a conspiracy against bone

“…Th17 cells synthesize IL-17 and express RANKL, both of which directly induce osteoclast differentiation (77,78). Additionally, IL-17 potentiates RANKL's osteoclastogenic capacity by upregulating RANK on osteoclast precursor cells (79). IL-17 also indirectly promotes bone destruction by inducing synovial fibroblasts and macrophages, respectively, to express TNF-α, IL-1, and IL-6 (80,81).…”

Induction of osteoclast progenitors in inflammatory conditions: key to bone destruction in arthritis

“…It is also produced by mast cells, a major source of IL-17 in inflammatory arthritis. In vitro, IL-17 stimulates osteoclastogenesis mostly indirectly by inducing RANKL expression (in osteoblasts and synovial fibroblasts) and production of proinflammatory cytokines (IL-6, IL-8, TNF-α and IL-1), but may also upregulate RANK in human OCPs and act in a RANKL-independent manner [68]. Some potent arthritic mediators exert their effects in synergy with IL-17, such as IL-23, which is able to elicit severe arthritis with a profound bone-resorptive phenotype.…”