title: AG490 suppresses interleukin-34-mediated osteoclastogenesis in mice bone marrow macrophages.
abstract: 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.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.|Department of Oral and Maxillofacial Trauma and Plastic Aesthetic Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Wan
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.|Department of Oral and Maxillofacial Trauma and Plastic Aesthetic Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Zu-Bing
authors.initials: ZB
authors.lastname: Li
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D007378:Interleukins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D007378:Interleukins; D016328:NF-kappa B; D053245:RANK Ligand; D050796:STAT3 Transcription Factor; C505689:Tnfsf11 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C552364:interleukin-34, mouse
keywords: AG490; IL-34; STAT3; Smad7; differentiation; osteoclast