Study of the correlation bone in osteoclast resorption with atopic disease

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Receptor activator of nuclear factor kB (RANK) ligand (RANKL), expressed by osteoblastic cells, plays a pivotal role in osteoclastogenesis as well as in osteoclast activation and survival. After RANKL binds to its receptor, RANK, several tumor necrosis factor receptor-associated factors (TRAFs) bind directly to the cytoplasmic domain of RANK. The interaction between TRAF and RANK appears to be responsible for initiating the activation of most of the RANK-mediated signaling pathways such as NF-kB, Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3K) and calcium signaling pathways. RANK occupancy mobilizes intracellular calcium, a requisite for calcineurin-mediated nuclear factor activated T cells (NFAT) activation. NFAT binds to its DNA response element via a ternary complex with AP-1 proteins, including Fos/Jun, to transactivate target genes including tartrate-resistant acid phosph … More atase (TRAP). Thus NF-kB, AP-1 and NFAT play essential roles in osteoclast differentiation, fusion and activation. In this study, non-toxic concentrations of pepstatin A suppressed the osteoclastogenesis in a dose-dependent manner, especially in an early stage of osteoclast formation. The concentration of pepstatin A required for the suppression of osteoclast formation was higher than that for the complete inhibition of the aspartic proteinase activity in intact cells. Namely, the inhibition of osteoclastgenesis by pepstatin A was independent of the activity for cathepsin D. A cell signaling analyses indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkB, Akt and p38 showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cell c1 (NFATc1). These results suggest that pepstatin A suppresses the differentiation of osteoclasts through the blockade of ERK signaling and the inhibition of NFATc1 expression, and such actions are not due to the inhibition of the cathepsin D activity. Less