Tumor necrosis factor-alpha induces differentiation of human peripheral blood mononuclear cells into osteoclasts through the induction of p21(WAF1/Cip1) |
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Authors: | Kwak Han Bok Jin Hye-Mi Ha Hyunil Kang Mi-Jin Lee Seung Bok Kim Hong-Hee Lee Zang Hee |
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Affiliation: | Research Center for Proteineous Materials, Chosun University, Gwangju 501-759, Republic of Korea. |
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Abstract: | Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that mediates inflammation and induces bone loss caused by excessive bone resorption by osteoclasts. The interaction of TNF-alpha with its receptor activates several signal transduction pathways, including those of mitogen-activated protein (MAP) kinases (p38, JNK, and ERK) and NF-kappaB. Signaling from these molecules has been shown to play an important role in osteoclastogenesis. In the present study, we investigated the mechanism of TNF-alpha-induced osteoclast differentiation in human peripheral blood mononuclear cells (PBMCs). We found that TNF-alpha alone greatly induced differentiation of PBMCs into osteoclasts. The osteoclast differentiation induced by TNF-alpha was independent of RANKL binding to its receptor RANK on PBMCs. Furthermore, TNF-alpha potently activated p38 MAPK, JNK, and NF-kappaB. Western blotting analysis revealed that p21(WAF1/Cip1), a cyclin-dependent kinase (CDK) inhibitor, is significantly induced upon TNF-alpha stimulation. The induction of p21(WAF1/Cip1) during differentiation is responsible for arrest at G(0)/G(1) phase and associated with the JNK pathway. These results suggest that TNF-alpha regulates osteoclast differentiation through p21(WAF1/Cip1) expression and further shows that these events require JNK activity. |
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Keywords: | TNF-α PBMC Osteoclast p21WAF1/Cip1 |
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