title: Piperine alleviates osteoclast formation through the p38/c-Fos/NFATc1 signaling axis.
abstract: Increased bone fracture is one of the health risk factors in patients with bone loss related disorders such as osteoporosis and breast cancer metastasis to bone. Over activity of osteoclasts leads to uncoupling of bone remodeling favoring bone loss over bone formation. Receptor activator of nuclear factor-κβ ligand (RANKL) triggers the differentiation pathway leading to multinucleated osteoclast formation. Modulation of RANKL or its downstream signaling pathways involved in osteoclast formation is of significant interest in the development of anti-resorptive agents. In this study, the effects of piperine, an alkaloid present in Piper nigrum L. on osteoclast formation was investigated. Piperine inhibited tartrate-resistant acid phosphatase-positive multinucleated osteoclast formation in murine RAW264.7 macrophages and human CD14+ monocytes induced by RANKL and breast cancer cells. Piperine attenuated the p38-mitogen activated protein kinase pathway activation, while the extracellular-signal-regulated kinase, c-Jun N-terminal kinase, or NF-κβ pathways downstream of RANKL remained unaffected. Concomitantly, expression of c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), the key transcription factors involved in osteoclastogenesis were remarkably inhibited by piperine. Furthermore, piperine disrupted the actin ring structure and bone resorption, a characteristic hallmark of osteoclasts. Collectively, these results suggested that piperine inhibited osteoclast differentiation by suppressing the p38/NFATc1/c-Fos signaling axis..
authors.affiliation: Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
authors.forename: Vishwa
authors.initials: V
authors.lastname: Deepak
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, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
authors.forename: Annie
authors.initials: A
authors.lastname: Joubert
authors.affiliation: Department of Physiology, 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: Magdalena
authors.initials: M
authors.lastname: Coetzee
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage*; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage*; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D016761:Oncogene Proteins v-fos / Q000096:biosynthesis / Q000235:genetics*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage*; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage*; D053245:RANK Ligand / Q000235:genetics; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D050778:NFATC Transcription Factors; D016761:Oncogene Proteins v-fos; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C008922:piperine
keywords: CD14+ monocytes; RANKL; RAW264.7; bone; breast cancer; osteoclast