title: Diarylheptanoid from Curcuma comosa Roxb. suppresses RANKL-induced osteoclast differentiation by decreasing NFATc1 and c-Fos expression via MAPK pathway.
abstract: Osteoporosis is caused by a functional imbalance between osteoblasts and osteoclasts. The increased activation of osteoclasts that is a hallmark of osteoporosis results in the progressive loss of bone mass and therefore in an increased susceptibility to bone fractures. Diarylheptanoids are a group of phytoestrogens that have been isolated from a number of plant species, including the rhizomes of Curcuma comosa Roxb. In this study, the effect of one of diarylheptanoids, (3S)-1-(3,4-dihydroxyphenyl)-3-hydroxy-7-phenyl-(6E)-6-heptene (DHPH), was investigated for anti-inflammatory and anti-osteoclastogenic activity. DHPH significantly inhibited nitric oxide production in RAW264.7 cell line following their activation by lipopolysaccharide and interferon-γ, with no cytotoxicity. In primary mouse bone-marrow-derived macrophage precursors, DHPH suppressed osteoclastogenesis induced by receptor activator of nuclear factor-κB (RANK) ligand at an inhibitory concentration 50 of 325±1.37nM. DHPH treatment delayed and reduced the expression of master regulators of osteoclast differentiation, NFATc1 and c-Fos. Consistent with this result, the mRNA level of cathepsin K, associated with osteoclast differentiation, was decreased whereas the reduction in the mRNA of irf8, a negative regulator of osteoclast differentiation, was similar to that measured in the vehicle-treated control cells. DHPH reduced the phosphorylation of p38 MAPK, ERK (p44/42). Furthermore, DHPH suppressed the bone absorption activity of osteoclasts and enhanced osteoblast differentiation. Taken together, DHPH interrupts the immediate downstream signaling cascade of RANK and interferes with osteoclast differentiation and its function while enhances osteoblast differentiation. These results demonstrate the potential of this diarylheptanoid as a new therapeutic agent in osteoporosis.
authors: Graduate Program in Biotechnology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok 10330, Thailand.
authors: Supatta
authors: S
authors: Chawalitpong
authors: Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Ramkhamhaeng Rd, Bang Kapi, Bangkok 10240, Thailand.
authors: Nilubon
authors: N
authors: Sornkaew
authors: Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Ramkhamhaeng Rd, Bang Kapi, Bangkok 10240, Thailand.
authors: Apichart
authors: A
authors: Suksamrarn
authors: Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok 10330, Thailand; Center of Excellence in Immunology and Immune-mediated Diseases, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok 10330, Thailand. Electronic address: tanapat.p@chula.ac.th.
authors: Tanapat
authors: T
authors: Palaga
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D030024:Curcuma / Q000737:chemistry; D036381:Diarylheptanoids / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D053245:RANK Ligand / Q000494:pharmacology*; D000067996:RAW 264.7 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D036381:Diarylheptanoids; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand
keywords: Diarylheptanoid; Fast red violet LB salt (PubChem CID: 16219357); Nephthol AS-MX phosphate (PubChem CID: 74136); Nuclear factor of activated T cells c1; Osteoclast; Receptor activator of nuclear factor-κB ligand; Toluene blue O (PubChem CID: 7083); Triton X-100 (PubChem CID: 5590); ascorbic acid (PubChem CID: 54670067); formaldehyde (PubChem CID: 712); p-nitrophenyl phosphate (PubChem CID: 468686); sulfanilamide (PubChem CID: 5333)