Paeonol inhibits RANKL-induced osteoclastogenesis by inhibiting ERK, p38 and NF-kappaB pathway.
Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with osteoporosis. Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of the traditionally used Chinese herb Paeonia lactiflora Pallas, has anti-inflammatory activity. Here we found that paeonol markedly inhibited the receptor activator of nuclear factor kappa B ligand (RANKL) plus macrophage colony stimulating factor (M-CSF)-induced osteoclastic differentiation from bone marrow stromal cells and RAW264.7 macrophage cells. In addition, in an assay of osteoclast activity on substrate plates, paeonol significantly decreased the resorption activity of mature osteoclasts. Treatment of RAW264.7 macrophages with RANKL induced extracellular signal-regulated kinases (ERK), p38 and c-Jun N-terminal kinase (JNK) phosphorylation. However, RANKL-induced ERK, p38 but not JNK phosphorylation was attenuated by paeonol. Furthermore, RANKL-mediated increase of IkappaBalpha phosphorylation, p65 phosphorylation at Ser(536), kappaB-luciferase activity and NF-kappaB binding activity was inhibited by paeonol. In addition, paeonol also prevented the bone loss inducing by ovariectomy in vivo. Our data suggest that paeonol inhibits osteoclastogenesis from bone marrow stromal cells and macrophage cells via attenuated of RANKL-induced ERK, p38 and NF-kappaB activation, which in turn protect bone loss from ovariectomy.
Tsai
Huei-Yann
HY
School of Pharmacy, China Medical University, Taichung, Taiwan.
Lin
Hui-Yi
HY
Fong
Yi-Chin
YC
Wu
Jin-Bin
JB
Chen
Yuh-Fung
YF
Tsuzuki
Minoru
M
Tang
Chih-Hsin
CH
D000098:Acetophenones / Q000494:pharmacology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D053495:Osteopontin / Q000378:metabolism; D010052:Ovariectomy; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000098:Acetophenones; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D015675:Osteocalcin; D053495:Osteopontin; C013638:paeonol; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000469:Alkaline Phosphatase