Glechoma hederacea Suppresses RANKL-mediated Osteoclastogenesis.
Glechoma hederacea (GH), commonly known as ground-ivy or gill-over-the-ground, has been extensively used in folk remedies for relieving symptoms of inflammatory disorders. However, the molecular mechanisms underlying the therapeutic action of GH are poorly understood. Here, we demonstrate that GH constituents inhibit osteoclastogenesis by abrogating receptor activator of nuclear κ-B ligand (RANKL)-induced free cytosolic Ca(2+) ([Ca(2+)]i) oscillations. To evaluate the effect of GH on osteoclastogenesis, we assessed the formation of multi-nucleated cells (MNCs), enzymatic activity of tartrate-resistant acidic phosphatase (TRAP), expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), and [Ca(2+)]i alterations in response to treatment with GH ethanol extract (GHE) in primarily cultured bone marrow-derived macrophages (BMMs). Treatment of RANKL-stimulated or non-stimulated BMMs with GHE markedly suppressed MNC formation, TRAP activity, and NFATc1 expression in a dose-dependent manner. Additionally, GHE treatment induced a large transient elevation in [Ca(2+)]i while suppressing RANKL-induced [Ca(2+)]i oscillations, which are essential for NFATc1 activation. GHE-evoked increase in [Ca(2+)]i was dependent on extracellular Ca(2+) and was inhibited by 1,4-dihydropyridine (DHP), inhibitor of voltage-gated Ca(2+) channels (VGCCs), but was independent of store-operated Ca(2+) channels. Notably, after transient [Ca(2+)] elevation, treatment with GHE desensitized the VGCCs, resulting in an abrogation of RANKL-induced [Ca(2+)]i oscillations and MNC formation. These findings demonstrate that treatment of BMMs with GHE suppresses RANKL-mediated osteoclastogenesis by activating and then desensitizing DHP-sensitive VGCCs, suggesting potential applications of GH in the treatment of bone disorders, such as periodontitis, osteoporosis, and rheumatoid arthritis.
Center for Metabolic Function Regulation (CMFR), Wonkwang University School of Medicine, Iksan 570-749, Republic of Korea Department of Oral Biochemistry, College of Dentistry, Wonkwang University, 344-2 Shinyong-dong, Iksan 570-749, Republic of Korea.
J K
JK
Hwang
Department of Oral Physiology, College of Dentistry, Wonkwang University, Iksan 570-749, Republic of Korea.
M
M
Erkhembaatar
Center for Metabolic Function Regulation (CMFR), Wonkwang University School of Medicine, Iksan 570-749, Republic of Korea Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan 570-749, Republic of Korea.
D R
DR
Gu
Center for Metabolic Function Regulation (CMFR), Wonkwang University School of Medicine, Iksan 570-749, Republic of Korea Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan 570-749, Republic of Korea.
S H
SH
Lee
Microelectronics and Display, Next Generation Industrial Radiation Technology RIC, Wonkwang University, Iksan 570-749, Republic of Korea.
C H
CH
Lee
Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752.
D M
DM
Shin
Center for Metabolic Function Regulation (CMFR), Wonkwang University School of Medicine, Iksan 570-749, Republic of Korea Department of Oral Biochemistry, College of Dentistry, Wonkwang University, 344-2 Shinyong-dong, Iksan 570-749, Republic of Korea mindyr@wku.ac.kr happy1487@wku.ac.kr.
Y R
YR
Lee
Department of Oral Physiology, College of Dentistry, Wonkwang University, Iksan 570-749, Republic of Korea Microelectronics and Display, Next Generation Industrial Radiation Technology RIC, Wonkwang University, Iksan 570-749, Republic of Korea mindyr@wku.ac.kr happy1487@wku.ac.kr.
M S
MS
Kim
D000135:Acid Phosphatase / Q000187:drug effects; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015726:Giant Cells / Q000187:drug effects; D007527:Isoenzymes / Q000187:drug effects; D019686:Lamiaceae; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D053245:RANK Ligand / Q000187:drug effects*; D000071681:Tartrate-Resistant Acid Phosphatase
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D010936:Plant Extracts; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C038806:1,4-dihydropyridine; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
NFATc1; [Ca2+]i oscillation; bone remodeling; natural product; osteoclast; periodontitis