Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-κB regulated HIF-1α and PGE(2) synthesis.
Icariin has been reported to enhance bone healing and treat osteoporosis. In this study, we examined the detail molecular mechanisms of icariin on lipopolysaccharide (LPS)-induced osteolysis. Our hypothesis is that icariin can inhibit osteoclast differentiation and bone resorption by suppressing MAPKs/NF-κB regulated HIF-1α and PGE(2) synthesis. After treatment with icariin, the activity of osteoclasts differentiation maker, tatrate resistances acid phosphatease (TRAP), significantly decreased at the concentration of 10(-8)M. Icariin (10(-8)M) reduced the size of LPS-induced osteoclasts formation, and diminished their TRAP and acid phosphatease (ACP) activity without inhibition of cell viability. Icariin also inhibited LPS-induced bone resorption and interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) expression. The gene expression of osteoprotegerin (OPG) was up-regulated, while receptor activator of NF-κB ligand (RANKL) was down-regulated. Icariin also inhibited the synthesis of cyclo-oxygenase type-2 (COX-2) and prostaglandin E(2) (PGE(2)). In addition, icariin had a dominant repression effect on LPS-induced hypoxia inducible factor-1α (HIF-1α) expression of osteoclasts. On osteoclasts, icariin suppresses LPS-mediated activation of the p38 and JNK; while on the osteoblasts, icariin reduced the LPS-induced activation of ERK1/2 and I-kappa-B-alpha (IκBα), but increased the activation of p38. In conclusion, we demonstrated that icariin has an in vitro inhibitory effects on osteoclasts differentiation that can prevent inflammatory bone loss. Icariin inhibited LPS-induced osteoclastogenesis program by suppressing activation of the p38 and JNK pathway.
Hsieh
Tsai-Pei
TP
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan, ROC.
Sheu
Shiow-Yunn
SY
Sun
Jui-Sheng
JS
Chen
Ming-Hong
MH
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D034181:Epimedium / Q000737:chemistry; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010014:Osteolysis / Q000139:chemically induced / Q000188:drug therapy; D010024:Osteoporosis / Q000378:metabolism / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D005419:Flavonoids; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053244:Osteoprotegerin; D010936:Plant Extracts; D053245:RANK Ligand; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C056599:icariin