Proteasome inhibitors induce osteoclast survival by activating the Akt pathway.
Osteoclasts rapidly undergo spontaneous apoptosis when deprived of survival factors. Regulation of osteoclast survival is important to treat bone-related diseases, such as osteoporosis. In this study, we found that the proteasome inhibitors, MG132 and ALLN, significantly inhibited osteoclast apoptosis induced by etoposide, as well as under conditions of survival factor deprivation. MG132 and ALLN inhibited the release of cytochrome c from mitochondria into the cytosol in the absence of survival factors and suppressed the cleavage of pro-caspase-9 and -3 to its active forms induced by etoposide. In addition, MG132 and ALLN enhanced the phosphorylation of Akt and ERK in osteoclasts. However, MG132 and ALLN did not inhibit the cleavage of caspase-9 and -3 in the presence of the phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002, while the inhibitory effect of MG132 and ALLN were intact in presence of the MEK1/2 inhibitor, U0126. LY294002 inhibited the survival of osteoclasts induced by MG132 and ALLN. Taken together, our results have demonstrated that proteasome inhibitors suppressed osteoclast apoptosis under conditions of survival factors deprivation through activation of the PI-3K/Akt pathway.
Kwak
Han Bok
HB
Department of Anatomy, School of Medicine, Wonkwang University College of Medicine, Iksan, Chonbuk, Republic of Korea.
Lee
Myeung Su
MS
Kim
Hun Soo
HS
Cho
Hae Joong
HJ
Kim
Jeung Woo
JW
Lee
Zang Hee
ZH
Oh
Jaemin
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002470:Cell Survival; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt