Selective upregulation of the ADP-ribosyl cyclases CD38 and CD157 by TNF but not by RANK-L reveals differences in downstream signaling.

In macrophages and osteoclast precursors, the cytokines TNF and RANK-L induce similar downstream pathways and share some of the same adaptor molecules. However, despite these similarities, no defined signaling schematic has emerged to show how each cytokine favors particular pathways. In this report, we investigate whether TNF and RANK-L differentially regulate ADP-ribosyl cyclases-enzymes that are unique in being crucial for immunological function yet detrimental to osteoclastogenesis. TNF but not RANK-L led to the sustained upregulation of both CD38 and CD157 as demonstrated by real-time PCR and flow cytometry. Further investigation demonstrated that this upregulation was a result of continuous, direct TNF signaling and involved JNK, and more critically PKC and NF-kappaB. Using this approach allowed us to highlight the relative importance of the PKC, NF-kappaB, and JNK pathways in actualizing proper outcomes of TNF signaling. Albeit speculative, we believe that differences between TNF- and RANK-l-induced activation of downstream signaling pathways, in particular PKC, are crucial for determining whether progenitor cells become geared for immunity or bone resorption.