Pyridone 6, a pan-Janus-activated kinase inhibitor, suppresses osteoclast formation and bone resorption through down-regulation of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced c-Fos and nuclear factor of activated T cells (NFAT) c1 expression.

Abstract

It has been reported that Janus tyrosine kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of numerous malignancies and immune reactions, and inhibition of JAK has been implicated in cell growth inhibition. The role which JAK has on osteoclast differentiation and anti-bone resorptive activity is not well understood. In this study, we investigated the effects of a pan-JAK inhibitor, pyridone 6, on osteoclast differentiation and bone-resorption in vitro and ex vivo. Pyridone 6 inhibited osteoclast differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It also inhibited the bone resorptive activity of mature osteoclasts that was accompanied by disruption of actin rings. Pyridone 6 also suppressed I-kappaB degradation and extracellular signal-regulated kinase (ERK) in mature osteoclasts, suggesting that these are the key molecules that pyridone 6 targets in the inhibition of osteoclast function. These results demonstrate inhibition of JAK may be useful for the treatment of bone-resorptive diseases, such as osteoporosis.

• Authors: Han Bok Kwak, Hun Soo Kim, Myeung Su Lee, Kwang-Jin Kim, Eun-Yong Choi, Min-Kyu Choi, Jeong-Joong Kim, Hae Joong Cho, Jeong Woo Kim, Ji-Myung Bae, Yun-Kyung Kim, Byoung Hyun Park, Hyunil Ha, Churl Hong Chun, Jaemin Oh
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 32 Issue 1 Pg. 45-50 (Jan 2009) ISSN: 0918-6158 [Print] Japan
• PMID: 19122279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one
• Benzimidazoles
• Enzyme Inhibitors
• NF-kappa B
• NFATC Transcription Factors
• Proto-Oncogene Proteins c-fos
• Pyridones
• RANK Ligand

Topics

• Animals
• Benzimidazoles (pharmacology)
• Bone Marrow Cells (drug effects)
• Bone Resorption (drug therapy)
• Cell Differentiation (drug effects)
• Cell Line, Transformed
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Macrophages (drug effects)
• Mice
• NF-kappa B (metabolism)
• NFATC Transcription Factors (genetics, metabolism)
• Osteoclasts (drug effects, physiology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Pyridones (pharmacology)
• RANK Ligand (metabolism)
• Signal Transduction (drug effects)