A novel PPARγ agonist,KR62776, suppresses RANKL-induced osteoclast differentiation and activity by inhibiting MAP kinase pathways |
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| Authors: | Ju-Young Park Myung-Ae Bae Hyae Gyeong Cheon Sung Soo Kim Jung-Min Hong Tae-Ho Kim Je-Yong Choi Sang-Hyun Kim Jiwon Lim Chang-Hyuk Choi Hong-In Shin Shin-Yoon Kim Eui Kyun Park |
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| Institution: | 1. Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu, Republic of Korea;2. Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;3. Center for Metabolic Syndrome Therapeutics, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea;4. Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;5. Department of Oral Pathology, IHBR, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea;6. Department of Orthopaedic Surgery, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea;7. Department of Orthopaedic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;1. National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada, Obihiro, Hokkaido 080-8555, Japan;2. Kenya Agricultural Research Institute, Trypanosomiasis Research Centre (KARI-TRC), P.O. Box 362-00902, Kikuyu, Kenya;3. Tohoku Medical Megabank Organization, Tohoku University, Aramaki Aza Aoba 6-3-09, Aoba-ku, Sendai, Miyagi 980-8579, Japan;4. Department of Protozoology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan;1. Institute of Electronic Engineering, China Academy of Engineering Physics, Mianyang, Sichuan, China;2. Center for Fuel Cell Innovation, School of Materials Science and Engineering, State Key Laboratory of Material Processing and Die & Mould Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China;1. Department of Oral and Maxillofacial Pathobiology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan;2. Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan;3. R&D Division, Sunstar Inc, Osaka, Japan;4. Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan;1. Departamento de Ingeniería Química, Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela 12, 13005 Ciudad Real, Spain;2. Université de Lorraine, Institut Jean Lamour, UMR7198, F-54011 Nancy, France;3. CNRS, Institut Jean Lamour, UMR7198, F-54011 Nancy, France |
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| Abstract: | We investigated the effects of a novel peroxisome proliferator-activated receptor γ (PPARγ) 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 αvβ3 integrin. An analysis of a signaling pathway showed that KR62776 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of p38 mitogen-activated protein kinase (p38MAPK), extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB). Together, these results demonstrate that KR62776 negatively affects osteoclast differentiation and activity by inhibiting the RANKL-induced activation of MAP kinases and NF-κB. |
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