title: Platelet-derived growth factor BB enhances osteoclast formation and osteoclast precursor cell chemotaxis.
abstract: Enhanced osteoclast formation increases bone resorption, which triggers bone remodeling. Platelet-derived growth factor BB (PDGF-BB) enhances precursor cell homing, angiogenesis, and bone healing, and thereby could also treat osteoporosis. However, the effect of PDGF-BB on osteoclast formation is not fully understood. We investigated whether exogenous recombinant PDGF-BB directly affects osteoclast formation and osteoclast precursor cell chemotaxis. The murine monocyte-macrophage cell line RAW264.7 and bone-marrow-derived macrophages were cultured with recombinant mouse PDGF-BB with or without a platelet-derived growth factor receptor β inhibitor (AG-1295) or a Janus kinase 2 inhibitor (AG-490) to analyze the effect on osteoclastogenesis in vitro. PDGF-BB with or without AG-490 or AG-1295 was locally administrated in the mandibular fracture of 16-week-old Sprague Dawley rats (n = 18) for 1-2 weeks to analyze the effect on osteoclastogenesis in vivo. The effect of the treatments on osteoclast formation, osteoclast precursor cell migration, and expression of osteoclastogenic signaling molecules was analyzed. PDGF-BB enhanced osteoclast formation both in vitro and in vivo, but AG-490 and AG-1295 inhibited this effect. PDGF-BB enhanced phosphorylation of extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, and signal transducer and activator of transcription 3 (STAT3) in RAW264.7 cells. AG-490 inhibited PDGF-BB-induced STAT3 phosphorylation. PDGF-BB enhanced RAW264.7 cell migration and gene expression of osteoclastogenic signaling molecules (i.e., nuclear factor of activated T cells 1, dendrocyte-expressed seven transmembrane protein, and B-cell lymphoma 2), and treatment with AG-1295, AG-490, or S3I-201 (a STAT3 inhibitor) reduced this effect. PDGF-BB enhanced osteoclast formation, osteoclast precursor cell chemotaxis, and phosphorylation of STAT3, Akt, and ERK1/2. but AG-1295 and AG-490 reduced this effect. These findings reflect the complexity of PDGF-BB in bone biology.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China.|Department of Oral and Maxillofacial Trauma and Plastic Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China.
authors.forename: Dian-Qi
authors.initials: DQ
authors.lastname: Li
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China.|Department of Oral and Maxillofacial Trauma and Plastic Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China.
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Wan
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, People's Republic of China.
authors.forename: Janak L
authors.initials: JL
authors.lastname: Pathak
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China. lizubing0827@163.com.|Department of Oral and Maxillofacial Trauma and Plastic Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China. lizubing0827@163.com.
authors.forename: Zu-Bing
authors.initials: ZB
authors.lastname: Li
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D001557:Benzenesulfonates / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C407689:6,7-dimethoxy-2-phenylquinoxaline; D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C520337:NSC 74859; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000077214:Becaplermin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Chemotaxis; Osteoclastogenesis; Osteoporosis; Phosphorylation; Platelet-derived growth factor BB