title: A novel PPARgamma agonist, KR62776, suppresses RANKL-induced osteoclast differentiation and activity by inhibiting MAP kinase pathways.
abstract: We investigated the effects of a novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, KR62776, on osteoclast differentiation and function, and on the underlying signaling pathways. KR62776 markedly suppressed differentiation into osteoclasts in various osteoclast model systems, including bone marrow mononuclear (BMM) cells and a co-culture of calvarial osteoblasts and BMM cells. KR62776 suppressed the activation of tartrate-resistant acid phosphatase (TRAP) and the expression of genes associated with osteoclast differentiation, such as TRAP, dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-associated receptor (OSCAR). Furthermore, KR62776 reduced resorption pit formation in osteoclasts, and down-regulated genes essential for osteoclast activity, such as Src and alphavbeta3 integrin. An analysis of a signaling pathway showed that KR62776 inhibited the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced activation of p38 mitogen-activated protein kinase (p38MAPK), extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB). Together, these results demonstrate that KR62776 negatively affects osteoclast differentiation and activity by inhibiting the RANKL-induced activation of MAP kinases and NF-kappaB.
authors.affiliation: Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Myung-Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Hong
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Kim
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jiwon
authors.initials: J
authors.lastname: Lim
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Choi
authors.forename: Hong-In
authors.initials: HI
authors.lastname: Shin
authors.forename: Shin-Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Eui Kyun
authors.initials: EK
authors.lastname: Park
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology
chemical_list: D007189:Indans; C534486:KR 62776; D010091:Oximes; D047495:PPAR gamma; D053245:RANK Ligand; D020929:Mitogen-Activated Protein Kinase Kinases