AG490 suppresses interleukin‐34‐mediated osteoclastogenesis in mice bone marrow macrophages

• Published in: Cell biology international Vol. 41; no. 6; pp. 659 - 668
• Main Authors: Cheng, Xin, Wan, Qi‐Long, Li, Zu‐Bing
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.06.2017
• Subjects: AG490; Animals; Bone marrow; Bone Marrow - metabolism; Bone Marrow Cells - metabolism; Cell Differentiation - drug effects; Colony-stimulating factor; Cytokines; differentiation; IL‐34; Interleukins - metabolism; Macrophage colony-stimulating factor; Macrophages; Macrophages - metabolism; Mice; Molecular modelling; NF-kappa B - metabolism; NF-κB protein; osteoclast; Osteoclastogenesis; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteomyelitis; RANK Ligand - metabolism; Rodents; Signal Transduction - drug effects; Smad7; Smad7 protein; STAT3; Stat3 protein; STAT3 Transcription Factor - metabolism; TRANCE protein; Tyrphostins - pharmacology; AG490; differentiation; IL-34; osteoclast; Smad7; STAT3
• ISSN: 1065-6995; 1095-8355
• DOI: 10.1002/cbin.10771

Interleukin‐34 (IL‐34) has been recently identified as a novel cytokine, substituting for the function of macrophage colony‐stimulating factor (M‐CSF), a pivotal osteoclastogenic factor involved in bone‐related diseases (e.g., osteomyelitis of the jaws). However, the molecular mechanisms are not fully understood. This study aimed to explore the potential mechanism of IL‐34 in receptor activator of NF‐kB ligand (RANKL)‐induced osteoclast formation. We found that IL‐34 alone significantly maintained the survival of bone marrow macrophages (BMMs) and enhanced the expression of the osteoclast‐related genes TRAP, Ctsk, and NFATc1, as well as TRAP‐positive multinucleated cells combined with RANKL, which can be reversed by AG490. Conversely, AG490 did not affect the M‐CSF‐mediated osteoclastogenesis in the presence of RANKL. The protein expression of p‐STAT3 in BMMs was enhanced by IL‐34 combined with RANKL compared with RANKL alone, and AG490 inhibited the expression of p‐SATA3 at protein level in the IL‐34 plus RANKL group, resulting in significantly increased Smad7 expression. This study demonstrated for the first time that IL‐34 may play a crucial role in RANKL‐induced osteoclastogenesis by promoting the proliferation and differentiation of BMMs, stimulating p‐STAT3 expression, and inhibiting the expression of Smad7 in the absence of M‐CSF.