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http://dx.doi.org/10.5483/BMBRep.2017.50.3.223

Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways  

Ihn, Hye Jung (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University)
Kim, Ju Ang (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University)
Bae, Yong Chul (Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University)
Shin, Hong-In (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University)
Baek, Moon-Chang (Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University)
Park, Eui Kyun (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University)
Publication Information
BMB Reports / v.50, no.3, 2017 , pp. 150-155 More about this Journal
Abstract
Non-small-cell lung cancer (NSCLC) is the third most common cancer that spreads to the bone, resulting in osteolytic lesions caused by hyperactivation of osteoclasts. Activating mutations in epidermal growth factor receptor-tyrosine kinase (EGF-TK) are frequently associated with NSCLC, and afatinib is a first-line therapeutic drug, irreversibly targeting EGF-TK. However, the effects of afatinib on osteoclast differentiation and activation as well as the underlying mechanism remain unclear. In this study, afatinib significantly suppressed receptor activator of nuclear factor ${\kappa}B$ (RANK) ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). Consistently, afatinib inhibited the expression of osteoclast marker genes, whereas, it upregulated the expression of negative modulator genes. The bone resorbing activity of osteoclasts was also abrogated by afatinib. In addition, afatinib significantly inhibited RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation. These results suggest that afatinib substantially suppresses osteoclastogenesis by downregulating RANK signaling pathways, and thus may reduce osteolysis after bone metastasis.
Keywords
Afatinib; Bone resorption; Differentiation; Osteoclast; RANK signaling;
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