Phosphodiesterase inhibitors stimulate osteoclast formation via TRANCE/RANKL expression in osteoblasts: possible involvement of ERK and p38 MAPK pathways
Phosphodiesterase inhibitors stimulate osteoclast formation via TRANCE/RANKL expression in osteoblasts: possible involvement of ERK and p38 MAPK pathways
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DOI：
10.1016/j.febslet.2004.12.066
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发表时间：
2005-01
期刊：
影响因子：
3.5
通讯作者：
M. Takami;E. S. Cho;Soo Young Lee;R. Kamijo;M. Yim
中科院分区：
文献类型：
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作者：
M. Takami;E. S. Cho;Soo Young Lee;R. Kamijo;M. Yim
磷酸二酯酶（PDE）是降解细胞内cAMP的酶。在本研究中，3-异丁基-1-甲基黄嘌呤（IBMX）和penoxifylline，PDE抑制剂，诱导破骨细胞形成的小鼠骨髓细胞和颅骨成骨细胞的共培养物。这些抑制剂诱导破骨细胞分化因子、TNF相关活化诱导细胞因子（TRANCE，等同于RANKL、ODF和OPGL）在颅骨成骨细胞中的表达。IBMX诱导成骨细胞中细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）磷酸化。IBMX诱导TRANCE表达被蛋白激酶A（PKA）、ERK和p38 MAPK抑制剂部分抑制，表明ERK和p38 MAPK以及PKA的激活参与了IBMX的TRANCE表达。成骨细胞表达PDE 4（PDE亚型），rolipram（PDE 4的选择性抑制剂）诱导TRANCE表达。这些结果表明，PDE 4是成骨细胞中TRANCE表达的关键调节因子，反过来又控制破骨细胞的形成。
Phosphodiesterases (PDEs) are enzymes that degrade intracellular cAMP. In the present study, 3-isobutyl-1-methylxanthine (IBMX) and pentoxifylline, PDE inhibitors, induced osteoclast formation in cocultures of mouse bone marrow cells and calvarial osteoblasts. These inhibitors induced the expression of the osteoclast differentiation factor, TNF-related activation induced cytokine (TRANCE, identical to RANKL, ODF, and OPGL), in calvarial osteoblasts. IBMX induced phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in osteoblasts. Induction of TRANCE expression by IBMX was partially suppressed by the inhibitors of protein kinase A (PKA), ERK, and p38 MAPK, suggesting that activation of ERK and p38 MAPK, as well as PKA, is involved in TRANCE expression by IBMX. Osteoblasts expressed PDE4, a PDE subtype, and rolipram, a selective inhibitor of PDE4, induced TRANCE expression. These results suggest that PDE4 is a key regulator of TRANCE expression in osteoblasts, which in turn controls osteoclast formation.