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) p21WAF1/CIP1 and p27KIP1 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 p21WAF1/CIP1 and p27KIP1 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 p21WAF1/CIP1 and p27KIP1 in osteoclastogenesis, accumulation of these CDK inhibitors was aborted by antisense oligonucleotides. Treatment with p21WAF1/CIP1 antisense oligonucleotide alone, or p27KIP1 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 p21WAF1/CIP1 and p27KIP1 may be involved in osteoclast differentiation induced by ODF/RANKL.
|Number of pages
|Journal of Cellular Biochemistry
|Published - 2001 Mar 1
- Cyclin-dependent kinase inhibitor
- p21 WAF1
- p27 KIP1