Inhibitory Effects of KP-A159, a Thiazolopyridine Derivative, on Osteoclast Differentiation, Function, and Inflammatory Bone Loss via Suppression of RANKL-Induced MAP Kinase Signaling PathwayReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

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.



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

Source: http://plos.srce.hr/



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