Anti-osteoclastogenic activity of matairesinol via suppression of p38/ERK-NFATc1 signaling axis.
BACKGROUND
Matairesinol is a plant lignan present in a wide variety of foodstuffs such as seeds, vegetables and fruits. It has various biological functions including anti-angiogenic, anti-cancer and anti-fungal activities, but its anti-osteoporotic activity, if any, is unknown.


METHODS
For osteoclast differentiation, primary mouse bone marrow-derived macrophage cells (BMMs) were cultured for 4 days in the presence of RANKL and M-CSF with the vehicle (DMSO) or matairesinol. Cell cytotoxicity was examined by CCK-8 assay. Gene expression of NFATc1, TRAP, OSCAR, v-ATPasev0d2 were observed in the presence or absence of matairesinol (10 μM) for the indicated times. For evaluating the involvement of NFATc1 in the anti-osteoclastogenic action of matairesinol, BMMs were infected with pMX-IRES-GFP or pMX-IRES-CA-NFATc1-GFP for 8 h with polybrene, and then infected BMMs were cultured with M-CSF and RANKL for 4 days in the presence or absence of matairesinol (10 μM). MAPK signaling activation was examined by immunoblotting. For measuring the resorptive activity of mature osteoclasts, osteoclasts and osteoblasts were co-cultured on BioCoat Osteologic MultiTest slides, and treated with matairesinol for 24 h.


RESULTS
Here we show that matairesinol dose-dependently inhibited the RANKL-induced differentiation of BMMs into osteoclasts by downregulating RANKL-induced expression and activity of NFATc1. Ectopic overexpression of NFATc1 blunted the anti-osteoclastogenic effect of matairesinol implicating NFATc1 in the action of matairesinol. Additionally, matairesinol blocked the RANKL-induced activation of p38 and ERK in BMMs, but had no effect on bone resorption activity in mature osteoclasts.


CONCLUSIONS
Taken together, our results suggest that the anti-osteoporotic activity of matairesinol could arise from its anti-osteoclastogenic potential via p38/ERK-NFATc1 signaling, but not by way of anti-resorptive action.
Sik-Won
SW
Choi
Kie-In
KI
Park
Jeong-Tae
JT
Yeon
Byung Jun
BJ
Ryu
Kwang-Jin
KJ
Kim
Laboratory of Translational Therapeutics, Pharmacology Research Center, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P,O, Box 107, Yuseong-gu, Daejeon 305-600, Korea. hwan@krict.re.kr.
Seong Hwan
SH
Kim
D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism* / Q000517:prevention & control; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D010945:Plants, Edible / Q000737:chemistry; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005663:Furans; D017705:Lignans; D050778:NFATC Transcription Factors; D010936:Plant Extracts; D053245:RANK Ligand; D014157:Transcription Factors; C068935:matairesinol; D016173:Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases