Esculetin attenuates receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation through c-Fos/nuclear factor of activated T-cells c1 signaling pathway

• Published in: Biochemical and biophysical research communications 2015-05, Vol.461 (2), p.334-341
• Main Authors: Baek, Jong Min, Park, Sun-Hyang, Cheon, Yoon-Hee, Ahn, Sung-Jun, Lee, Myeung Su, Oh, Jaemin, Kim, Ju-Young
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ACID PHOSPHATASE; ACTIN; Actins - metabolism; Actins - ultrastructure; Animals; BIOLOGICAL EFFECTS; c-Fos; CALCITONIN; CATHEPSINS; Cell Differentiation - drug effects; Cells, Cultured; Coculture Techniques; CONNECTIVE TISSUE CELLS; DENDRITES; Esculetin; F-actin ring; Humans; IN VITRO; INFLAMMATION; INHIBITION; LIGANDS; Male; MESSENGER-RNA; METABOLISM; Mice; NEOPLASMS; NF-kappa B - metabolism; NFATC Transcription Factors - antagonists & inhibitors; NFATC Transcription Factors - metabolism; NFATc1; Osteoclast; Osteoclasts - cytology; Osteoclasts - drug effects; Proto-Oncogene Proteins c-fos - antagonists & inhibitors; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand - metabolism; RECEPTORS; RINGS; Signal Transduction - drug effects; SIGNALS; SKELETAL DISEASES; TRANSCRIPTION FACTORS; Umbelliferones - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.04.034

Esculetin exerts various biological effects on anti-oxidation, anti-tumors, and anti-inflammation. However, the involvement of esculetin in the bone metabolism process, particularly osteoclast differentiation has not yet been investigated. In the present study, we first confirmed the inhibitory effect of esculetin on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. We then revealed the relationship between esculetin and the expression of osteoclast-specific molecules to elucidate its underlying mechanisms. Esculetin interfered with the expression of c-Fos and nuclear factor of activated T cell c1 (NFATc1) both at the mRNA and protein level with no involvement in osteoclast-associated early signaling pathways, suppressing the expression of various transcription factors exclusively expressed in osteoclasts such as tartrate-resistant acid phosphatase (Trap), osteoclast-associated receptor (Oscar), dendritic cell-specific transmembrane protein (Dcstamp), osteoclast stimulatory transmembrane protein (Ocstamp), cathepsin K, αvβ3 integrin, and calcitonin receptor (Ctr). Additionally, esculetin inhibited the formation of filamentous actin (F-actin) ring-positive osteoclasts during osteoclast differentiation. However, the development of F-actin structures and subsequent bone resorbing activity of mature osteoclasts, which are observed in osteoclast/osteoblast co-culture systems were not affected by esculetin. Taken together, our results indicate for the first time that esculetin inhibits RANKL-mediated osteoclastogenesis via direct suppression of c-Fos and NFATc1 expression and exerts an inhibitory effect on actin ring formation during osteoclastogenesis. [Display omitted] •We first investigated the effects of esculetin on osteoclast differentiation and function.•Our data demonstrate for the first time that esculetin can suppress osteoclastogenesis in vitro.•Esculetin acts as an inhibitor of c-Fos and NFATc1 activation.•Esculetin acts a negative regulator of actin ring formation during osteoclast differentiation.•Esculetin deserves new evaluation as a potential treatment target in various bone diseases.