title: Inhibitory Effects of KP-A159, a Thiazolopyridine Derivative, on Osteoclast Differentiation, Function, and Inflammatory Bone Loss via Suppression of RANKL-Induced MAP Kinase Signaling Pathway.
abstract: Abnormally elevated formation and activation of osteoclasts are primary causes for a majority of skeletal diseases. In this study, we found that KP-A159, a newly synthesized thiazolopyridine derivative, inhibited osteoclast differentiation and function in vitro, and inflammatory bone loss in vivo. KP-A159 did not cause a cytotoxic response in bone marrow macrophages (BMMs), but significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). KP-A159 also dramatically inhibited the expression of marker genes related to osteoclast differentiation, including TRAP (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), matrix metallopeptidase 9 (Mmp9), and nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Moreover, actin ring and resorption pit formation were inhibited by KP-A159. Analysis of the signaling pathway involved showed that KP-A159 inhibited RANKL-induced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase1/2 (MEK1/2). In a mouse inflammatory bone loss model, KP-A159 significantly rescued lipopolysaccharide (LPS)-induced bone loss by suppressing osteoclast numbers. Therefore, KP-A159 targets osteoclasts, and may be a potential candidate compound for prevention and/or treatment of inflammatory bone loss.
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Ihn
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Doohyun
authors.initials: D
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Taeho
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Hong-In
authors.initials: HI
authors.lastname: Shin
authors.affiliation: Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Skeletal Diseases Genome Research Centre, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Hong
authors.affiliation: Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Eui Kyun
authors.initials: EK
authors.lastname: Park
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000473:pathology*; D002454:Cell Differentiation; D015870:Gene Expression; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism / Q000502:physiology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011725:Pyridines; D053245:RANK Ligand; D013844:Thiazoles; C505689:Tnfsf11 protein, mouse