A novel PPARgamma agonist, KR62776, suppresses RANKL-induced osteoclast differentiation and activity by inhibiting MAP kinase pathways.
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.
Park
Ju-Young
JY
Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu, Republic of Korea.
Bae
Myung-Ae
MA
Cheon
Hyae Gyeong
HG
Kim
Sung Soo
SS
Hong
Jung-Min
JM
Kim
Tae-Ho
TH
Choi
Je-Yong
JY
Kim
Sang-Hyun
SH
Lim
Jiwon
J
Choi
Chang-Hyuk
CH
Shin
Hong-In
HI
Kim
Shin-Yoon
SY
Park
Eui Kyun
EK
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
D007189:Indans; C534486:KR 62776; D010091:Oximes; D047495:PPAR gamma; D053245:RANK Ligand; D020929:Mitogen-Activated Protein Kinase Kinases