Obatoclax Regulates the Proliferation and Fusion of Osteoclast Precursors through the Inhibition of ERK Activation by RANKL
- Authors
- Oh, Ju Hee; Lee, Jae Yoon; Park, Jin Hyeong; No, Jeong Hyeon; Lee, Na Kyung
- Issue Date
- Mar-2015
- Publisher
- 한국분자세포생물학회
- Keywords
- ERK1/2 MAP kinase; fusion; obatoclax; osteoclast precursors; proliferation
- Citation
- Molecules and Cells, v.38, no.3, pp 279 - 284
- Pages
- 6
- Journal Title
- Molecules and Cells
- Volume
- 38
- Number
- 3
- Start Page
- 279
- End Page
- 284
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/10823
- DOI
- 10.14348/molcells.2015.2340
- ISSN
- 1016-8478
0219-1032
- Abstract
- Obatoclax, a pan-Bcl2 inhibitor, shows antitumor activities in various solid malignancies. Bcl2-deficient mice have shown the importance of Bcl2 in osteoclasts, as the bone mass of the mice was increased by the induced apoptosis of osteoclasts. Despite the importance of Bcl2, the effects of obatoclax on the proliferation and differentiation of osteoclast precursors have not been studied extensively. Here, we describe the anti-proliferative effects of obatoclax on osteoclast precursors and its negative role on fusion of the cells. Stimulation with low doses of obatoclax significantly suppressed the proliferation of osteoclast precursors in a dose-dependent manner while the apoptosis was markedly increased. Its stimulation was sufficient to block the activation of ERK MAP kinase by RANKL. The same was true when PD98059, an ERK inhibitor, was administered to osteoclast precursors. The activation of JNK1/2 and p38 MAP kinase, necessary for osteoclast differentiation, by RANKL was not affected by obatoclax. Interestingly, whereas the number of TRAP-positive mononuclear cells was increased by both obatoclax and PD98059, fused, multinucleated cells larger than 100 mu m in diameter containing more than 20 nuclei were completely reduced. Consistently, obatoclax failed to regulate the expression of osteoclast marker genes, including c-Fos, TRAP, RANK and CtsK. Instead, the expression of DC-STAMP and Atp6v0d2, genes that regulate osteoclast fusion, by RANKL was significantly abrogated by both obatoclax and PD98059. Taken together, these results suggest that obatoclax down-regulates the proliferation and fusion of osteoclast precursors through the inhibition of the ERK1/2 MAP kinase pathway.
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Collections - College of Medical Sciences > Department of Biomedical Laboratory Science > 1. Journal Articles
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