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KMID : 0811720120160010031
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Korean Journal of Physiology & Pharmacology
2012 Volume.16 No. 1 p.31 ~ p.36
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Effects of Inositol 1,4,5-triphosphate on Osteoclast Differentiation in RANKL-induced Osteoclastogenesis
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Son A-ran
Kim Min-Seuk
Jo Hae
Byun Hae-Mi
Shin Dong-Min
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Abstract
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The receptor activator of NF-?B ligand (RANKL) signal is an activator of tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of NF-?B and other signal transduction pathways essential for osteoclastogenesis, such as Ca2＋ signaling. However, the intracellular levels of inositol 1,4,5-trisphosphate (IP3) and IP3-mediated cellular function of RANKL during osteoclastogenesis are not known. In the present study, we determined the levels of IP3 and evaluated IP3-mediated osteoclast differentiation and osteoclast activity by RANKL treatment of mouse leukemic macrophage cells (RAW 264.7) and mouse bone marrow-derived monocyte/macrophage precursor cells (BMMs). During osteoclastogenesis, the expression levels of Ca2＋ signaling proteins such as IP3 receptors (IP3Rs), plasma membrane Ca2＋ ATPase, and sarco/endoplasmic reticulum Ca2＋ ATPase type2 did not change by RANKL treatment for up to 6 days in both cell types. At 24 h after RANKL treatment, a higher steady-state level of IP3 was observed in RAW264.7 cells transfected with green fluorescent protein (GFP)-tagged pleckstrin homology (PH) domains of phospholipase C (PLC) ?, a probe specifically detecting intracellular IP3 levels. In BMMs, the inhibition of PLC with U73122 [a specific inhibitor of phospholipase C (PLC)] and of IP3Rs with 2-aminoethoxydiphenyl borate (2APB; a non-specific inhibitor of IP3Rs) inhibited the generation of RANKL-induced multinucleated cells and decreased the bone-resorption rate in dentin slice, respectively. These results suggest that intracellular IP3 levels and the IP3-mediated signaling pathway play an important role in RANKL-induced osteoclastogenesis.
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KEYWORD
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Inositol 1, 4, 5-trisphosphate, RANKL, Osteoclastogenesis, Ca2＋ signaling
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