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

Hye Jung Ihn; Doohyun Lee; Taeho Lee; Sang-Hyun Kim; Hong-In Shin; Yong Chul Bae; Jung Min Hong; Eui Kyun Park

doi:10.1371/journal.pone.0142201

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

PLoS One. 2015 Nov 4;10(11):e0142201. doi: 10.1371/journal.pone.0142201. eCollection 2015.

Authors

Hye Jung Ihn¹, Doohyun Lee², Taeho Lee², Sang-Hyun Kim¹, Hong-In Shin³, Yong Chul Bae⁴, Jung Min Hong⁵, Eui Kyun Park³

Affiliations

¹ Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
² College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
³ Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Republic of Korea.
⁴ Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
⁵ Skeletal Diseases Genome Research Centre, Kyungpook National University Hospital, Daegu, Republic of Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Resorption / pathology*
Cell Differentiation
Gene Expression
Gene Expression Regulation
MAP Kinase Signaling System*
Mice
Mice, Inbred C57BL
Osteoclasts / cytology
Osteoclasts / drug effects*
Pyridines / chemistry
Pyridines / pharmacology*
RANK Ligand / metabolism
RANK Ligand / physiology
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Pyridines
RANK Ligand
Thiazoles
Tnfsf11 protein, mouse

Grants and funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (2008-0062282). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.