Gymnasterkoreayne F inhibits osteoclast formation by suppressing NFATc1 and DC-STAMP expression.
Osteoclasts are multinucleated cells that have a unique role in bone degradation. Modulation of osteoclast formation and/or its activity is an important approach for the treatment of bone-destructive diseases such as osteoporosis and rheumatoid arthritis. In this study, Gymnasterkoreayne F (GK-F), a natural compound isolated from Gymnaster koraiensis, was found to inhibit osteoclast differentiation from primary bone marrow-derived macrophages (BMMs) in a dose-dependent manner. The inhibition occurred through the suppression of nuclear factor of activated T cells c1 (NFATc1) expression, which then led to the decreased levels of osteoclastogenic markers, including Cathepsin K and tartrate-resistant acid phosphatase (TRAP). In addition, GK-F abolished pre-osteoclast fusion induced by the receptor activator of nuclear factor kappa B ligand (RANKL), lipopolysaccharide (LPS) and TNF-α. Reflecting its inhibitory effects on cell-cell fusion, GK-F attenuated the gene expression of an essential molecule of osteoclast fusion, the dendritic cell-specific transmembrane protein (DC-STAMP). Furthermore, GK-F inhibited the bone resorptive activity of differentiated osteoclasts through its ability to block RANKL-induced actin ring formation. The effect was associated with a significant decrease in the induction of β3 integrin expression, which is an essential regulator of osteoclast cytoskeletal function. Taken together, these results suggest that GK-F might be useful as a therapeutic agent for bone resorption-related diseases.
Kim
Hyun-Ju
HJ
Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Jung-gu, Daegu, Republic of Korea. biohjk@knu.ac.kr
Hong
JungMin
J
Jung
Ji-Won
JW
Kim
Tae-Ho
TH
Kim
Jeong Ah
JA
Kim
Young Ho
YH
Kim
Shin-Yoon
SY
D000135:Acid Phosphatase / Q000032:analysis; D000199:Actins / Q000378:metabolism; D000818:Animals; D056657:Cathepsin K / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D002478:Cells, Cultured; D006173:Gymnastics; D039661:Integrin beta3 / Q000032:analysis / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D053279:Polyynes / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000199:Actins; C499636:DC-STAMP protein, mouse; D039661:Integrin beta3; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C556221:gymnasterkoreayne F; D053279:Polyynes; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K