Platelet-derived growth factor BB enhances osteoclast formation and osteoclast precursor cell chemotaxis

J Bone Miner Metab. 2017 Jul;35(4):355-365. doi: 10.1007/s00774-016-0773-8. Epub 2016 Sep 14.

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.

Keywords: Chemotaxis; Osteoclastogenesis; Osteoporosis; Phosphorylation; Platelet-derived growth factor BB.

MeSH terms

  • Aminosalicylic Acids / pharmacology
  • Animals
  • Becaplermin
  • Benzenesulfonates / pharmacology
  • Cells, Cultured
  • Chemotaxis / drug effects*
  • Chemotaxis / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteogenesis / drug effects
  • Osteogenesis / genetics
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-sis / pharmacology*
  • RAW 264.7 Cells
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tyrphostins / pharmacology

Substances

  • 6,7-dimethoxy-2-phenylquinoxaline
  • Aminosalicylic Acids
  • Benzenesulfonates
  • NSC 74859
  • Proto-Oncogene Proteins c-sis
  • STAT3 Transcription Factor
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Becaplermin
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases