TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in mouse osteoblastic MC3T3-E1 cells

Arthritis Res Ther. 2006;8(5):R146. doi: 10.1186/ar2038.

Abstract

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multifunctional cytokine that regulates cell growth, migration, and survival principally through a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14). However, its physiological roles in bone are largely unknown. We herein report various effects of TWEAK on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed Fn14 and produced RANTES (regulated upon activation, healthy T cell expressed and secreted) upon TWEAK stimulation through PI3K-Akt, but not nuclear factor-kappaB (NF-kappaB), pathway. In addition, TWEAK inhibited bone morphogenetic protein (BMP)-2-induced expression of osteoblast differentiation markers such as alkaline phosphatase through mitogen-activated protein kinase (MAPK) Erk pathway. Furthermore, TWEAK upregulated RANKL (receptor activation of NF-kappaB ligand) expression through MAPK Erk pathway in MC3T3-E1 cells. All these effects of TWEAK on MC3T3-E1 cells were abolished by mouse Fn14-Fc chimera. We also found significant TWEAK mRNA or protein expression in osteoblast- and osteoclast-lineage cell lines or the mouse bone tissue, respectively. Finally, we showed that human osteoblasts expressed Fn14 and induced RANTES and RANKL upon TWEAK stimulation. Collectively, TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in MC3T3-E1 cells. TWEAK may thus be a novel cytokine that regulates several aspects of osteoblast function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / pharmacology*
  • Cell Differentiation / drug effects
  • Chemokine CCL5 / metabolism*
  • Chimera
  • Cytokine TWEAK
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Humans
  • Mice
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RANK Ligand / genetics*
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • TWEAK Receptor
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / metabolism*
  • Tumor Necrosis Factors / pharmacology

Substances

  • BMP2 protein, human
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Chemokine CCL5
  • Cytokine TWEAK
  • RANK Ligand
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNFRSF12A protein, human
  • TNFSF11 protein, human
  • TWEAK Receptor
  • Tnfrsf12a protein, mouse
  • Tnfsf11 protein, mouse
  • Tnfsf12 protein, mouse
  • Transforming Growth Factor beta
  • Tumor Necrosis Factors
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt