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Osteoclast differentiation is associated with transient upregulation of cyclin‐dependent kinase inhibitors p21 WAF1/CIP1 and p27 KIP1
Author(s) -
Okahashi Nobuo,
Murase Yoshiyuki,
Koseki Takeyoshi,
Sato Tsuyoshi,
Yamato Kenji,
Nishihara Tatsuji
Publication year - 2000
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/1097-4644(20010301)80:3<339::aid-jcb60>3.0.co;2-#
Subject(s) - osteoclast , rankl , cyclin dependent kinase , macrophage colony stimulating factor , kinase , cdk inhibitor , multinucleate , chemistry , cancer research , microbiology and biotechnology , cellular differentiation , biology , macrophage , cell cycle , cyclin dependent kinase 2 , cell , protein kinase a , biochemistry , activator (genetics) , receptor , in vitro , gene
Osteoclasts, bone‐resorbing multinucleated cells, develop from monocyte‐macrophage lineage cells in the presence of osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) and macrophage colony‐stimulating factor (M‐CSF). M‐CSF‐dependent bone marrow macrophages (M‐BMMΦs) from mouse bone marrow cells have been shown to differentiate into osteoclast‐like multinucleated cells (OCLs) in the presence of soluble ODF/RANKL (sODF/RANKL) and M‐CSF within 3 days. In this study, we found that stimulation of M‐BMMΦs with sODF/RANKL induced a transient expression of cyclin‐dependent kinase inhibitors (CDK inhibitors) p21 WAF1/CIP1 and p27 KIP1 by 24 h. The CDK inhibitor proteins disappeared by 48 h. Tumor necrosis factor alpha (TNF‐α), which is reported to stimulate OCL differentiation, stimulated p21 WAF1/CIP1 and p27 KIP1 expression in M‐BMMΦs as well. However, M‐CSF alone did not stimulate the expression of the two CDK inhibitors. To clarify the role of p21 WAF1/CIP1 and p27 KIP1 in osteoclastogenesis, accumulation of these CDK inhibitors was aborted by antisense oligonucleotides. Treatment with p21 WAF1/CIP1 antisense oligonucleotide alone, or p27 KIP1 antisense oligonucleotide alone, showed a limited inhibitory effect on OCL formation. However, treatment with a mixture of these two antisense oligonucleotides strongly inhibited OCL formation. These results suggest that a combined modulation of the CDK inhibitors p21 WAF1/CIP1 and p27 KIP1 may be involved in osteoclast differentiation induced by ODF/RANKL. J. Cell. Biochem. 80:339–345, 2001. © 2001 Wiley‐Liss, Inc.