Crosstalk among interleukin 23 and DNAX activating protein 12-dependentpathways promotes osteoclastogenesis

Interleukin 23 (IL-23) has been well studied in the context of T cell differentiation, however, its role in the differentiation of myeloid progenitors is less clear. In this paper we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human peripheral blood mononuclear cells IL-23 induces the expression of MDL-1 a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DAP12 and its immunoreceptor tyrosine activation motifs (ITAM’s). The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on SYK and PLCγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor nuclear factor of activated T cells cytoplasmic 1 (NFATc1). IL-23 elicited osteoclastogenesis is independent of the RANKL pathway and utilizes a unique MDL-1+/DAP12+ cell subset. Our data define a novel pathway that is utilized by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.