title: Ellagic acid inhibits RANKL-induced osteoclast differentiation by suppressing the p38 MAP kinase pathway.
abstract: Bone undergoes continuous remodeling by a coupled action between osteoblasts and osteoclasts. During osteoporosis, osteoclast activity is often elevated leading to increased bone destruction. Hence, osteoclasts are deemed as potential therapeutic targets to alleviate bone loss. Ellagic acid (EA) is a polyphenol reported to possess anticancer, antioxidant and anti-inflammatory properties. However, its effects on osteoclast formation and function have not yet been examined. Here, we explored the effects of EA on RANKL-induced osteoclast differentiation in RAW264.7 murine macrophages (in vitro) and human CD14+monocytes (ex vivo). EA dose-dependently attenuated RANKL-induced TRAP+osteoclast formation in osteoclast progenitors with maximal inhibition seen at 1 µM concentration without cytotoxicity. Moreover, owing to perturbed osteoclastogenesis, EA disrupted actin ring formation and bone resorptive function of osteoclasts. Analysis of the underlying molecular mechanisms revealed that EA suppressed the phosphorylation and activation of the p38 MAP kinase pathway which subsequently impaired the RANKL-induced differentiation of osteoclast progenitors. Taken together, these novel results indicate that EA alleviates osteoclastogenesis by suppressing the p38 signaling pathway downstream of RANKL and exerts inhibitory effects on bone resorption and actin ring formation.
authors.affiliation: Department of Physiology, University of Pretoria, Private Bag X323, Arcadia, Pretoria, 0007, South Africa.
authors.forename: Mpho
authors.initials: M
authors.lastname: Rantlha
authors.affiliation: Department of Physiology, University of Pretoria, Private Bag X323, Arcadia, Pretoria, 0007, South Africa.
authors.forename: Travers
authors.initials: T
authors.lastname: Sagar
authors.affiliation: School of Food and Nutrition, Massey Institute of Food Science and Technology, Massey University, Palmerston North, New Zealand.|Department of Human Nutrition, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.|Associate of the Institute for Food, Nutrition and Well-being, University of Pretoria, Pretoria, South Africa.
authors.forename: Marlena C
authors.initials: MC
authors.lastname: Kruger
authors.affiliation: Department of Physiology, University of Pretoria, Private Bag X323, Arcadia, Pretoria, 0007, South Africa. magdalena.coetzee@up.ac.za.|Associate of the Institute for Food, Nutrition and Well-being, University of Pretoria, Pretoria, South Africa. magdalena.coetzee@up.ac.za.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Coetzee
authors.affiliation: Department of Physiology, University of Pretoria, Private Bag X323, Arcadia, Pretoria, 0007, South Africa. vishwa.deepak@nuigalway.ie.|Biomechanics Research Centre, Department of Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland. vishwa.deepak@nuigalway.ie.
authors.forename: Vishwa
authors.initials: V
authors.lastname: Deepak
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004610:Ellagic Acid / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology*; D053245:RANK Ligand / Q000494:pharmacology*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D004610:Ellagic Acid; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Ellagic acid; Macrophage; Monocyte; Osteoclast; Osteoporosis; RANKL