RANKL (receptor activator of NF-B ligand) induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration ofBone is a dynamic tissue that is constantly being remodeled. The remodeling process is a delicate balance between the activities of osteoblasts and osteoclasts. Interference with this balance results in serious human pathologies that affect bone integrity. Tipping the balance in favor of osteoclasts leads to pathological bone resorption, which is observed in autoimmune arthritis, osteoporosis, and periodontitis (1, 2).Bone marrow-derived monocyte/macrophage precursor cells (BMM) 2 of a hematopoietic origin develop into osteoclasts through cell-to-cell signaling with mesenchymal cells, such as osteoblasts (3, 4). Cell-to-cell interaction between the osteoclast precursors and osteoblastic/stromal cells are also essential for the differentiation of osteoclast progenitor cells into mature osteoclasts (5, 6). RANKL (receptor activator of NF-B ligand) is expressed in osteoblastic/stromal cells and is vital for osteoclast differentiation (7-11). Stimulation of the RANK receptor by RANKL in the presence of the macrophage colonystimulating factor (M-CSF) causes osteoclast differentiation and activation in vitro (6,8,12). Moreover, the binding of RANKL to its receptor results in the recruitment of the TNF receptor-associated factor (TRAF) family of proteins, e.g. TRAF6, which are linked to the NF-B and JNK pathways (13-15). Of particular importance, a series of signals following RANK activation induce oscillations in the free intracellular concentration of Ca 2ϩ ([Ca 2ϩ ] i ), which trigger the late stage of osteoclast differentiation by activating the nuclear factor of activated T cells type c1 (NFATc1) (16). Unique aspects of these RANKL-stimulated Ca 2ϩ oscillations is that they are observed only 24 -48 h post-stimulation, indicating the need for induction of the pathway responsible for the Ca 2ϩ oscillations. The nature of this pathway and how it is induced are not known. Ca 2ϩ is a ubiquitous intracellular messenger that mediates a wide variety of cellular functions and is involved in the fundamental cellular processes of proliferation, differentiation, and programmed cell death (17). In the case of osteoclast differentiation, Ca 2ϩ plays an important role by sequentially activating calcineurin and NFATc1 (16). Members of the NFAT family are among the most strongly induced transcription factors following RANKL stimulation. During osteoclastogenesis, costimulatory signals mediated by the immunoreceptor tyrosine-based

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Background and Aims-Receptor-stimulated Ca 2+ influx is a critical component of the Ca 2+ signal and mediates all cellular functions regulated by Ca 2+ . However, excessive Ca 2+ influx is highly toxic resulting in cell death, which is the nodal point in all forms of pancreatitis. Ca 2+ influx is mediated by store-operated channels (SOCs). The identity and function of the native SOCs in most cells is unknown.

Protease-activated receptor-2 (PAR-2) is known to be involved in epidermal permeability barrier function homeostasis. PAR-2 activation occurs after barrier disruption and further activation of PAR-2 by activating peptide significantly delays barrier recovery rate. Cockroach and house dust mite allergens, both known to be associated with the development of asthma, allergic rhinitis, and atopic dermatitis, have protease activity, which can activate PAR-2. In this study, we investigated the effects of both allergens on the epidermal barrier function as well as on the epidermal calcium gradient. Both allergens, when topically applied on the barrier-disrupted site, increased protease activities in the epidermis and delayed barrier recovery and lamellar body secretion in murine skin. The topical application of PAR-2-specific antagonist or protease inhibitors normalized the barrier recovery. Cockroach allergens induced intracellular calcium oscillations in cultured human keratinocytes through PAR-2-involved pathway, which was confirmed by desensitization protocol. Abnormal calcium ion distribution after barrier disruption was also observed in allergens-applied skin. These results suggest that allergens with protease activity can influence the epidermal permeability barrier homeostasis through PAR-2 activation and consequent modulation of the calcium ions in skin.

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