Dynein light chain LC8 inhibits osteoclast differentiation and prevents bone loss in mice

J Immunol. 2013 Feb 1;190(3):1312-8. doi: 10.4049/jimmunol.1202525. Epub 2013 Jan 4.

Abstract

NF-κB is one of the key transcription factors activated by receptor activator of NF-κB ligand (RANKL) during osteoclast differentiation. The 8-kDa dynein L chain (LC8) was previously identified as a novel NF-κB regulator. However, its physiological role as an NF-κB inhibitor remains elusive. In this study, we showed the inhibitory role of LC8 in RANKL-induced osteoclastogenesis and signaling pathways and its protective role in osteolytic animal models. LC8 suppressed RANKL-induced osteoclast differentiation, actin ring formation, and osteoclastic bone resorption. LC8 inhibited RANKL-induced phosphorylation and subsequent degradation of IκBα, the expression of c-Fos, and the consequent activation of NFATc1, which is a pivotal determinant of osteoclastogenesis. LC8 also inhibited RANKL-induced activation of JNK and ERK. LC8-transgenic mice exhibited a mild osteopetrotic phenotype. Moreover, LC8 inhibited inflammation-induced bone erosion and protected against ovariectomy-induced bone loss in mice. Thus, our results suggest that LC8 inhibits osteoclast differentiation by regulating NF-κB and MAPK pathways and provide the molecular basis of a new strategy for treating osteoporosis and other bone diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Animals
  • Bone Resorption / prevention & control*
  • Cell Differentiation
  • Cytoplasmic Dyneins / genetics
  • Cytoplasmic Dyneins / physiology*
  • Cytoplasmic Dyneins / toxicity
  • Drug Evaluation, Preclinical
  • Enzyme Activation
  • Gene Expression Regulation / physiology
  • Genes, fos
  • Humans
  • I-kappa B Proteins / metabolism
  • MAP Kinase Signaling System / physiology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / biosynthesis
  • NFATC Transcription Factors / genetics
  • Osteoclasts / pathology*
  • Osteolysis / physiopathology
  • Osteolysis / prevention & control*
  • Osteopetrosis / genetics
  • Osteoporosis, Postmenopausal / physiopathology
  • Osteoporosis, Postmenopausal / prevention & control
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • RANK Ligand / antagonists & inhibitors*
  • Recombinant Fusion Proteins / physiology
  • Recombinant Fusion Proteins / toxicity
  • Signal Transduction / physiology*

Substances

  • Actins
  • I-kappa B Proteins
  • NF-kappa B
  • NFATC Transcription Factors
  • NFKBIA protein, human
  • Nfatc1 protein, mouse
  • Nfkbia protein, mouse
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Recombinant Fusion Proteins
  • Tnfsf11 protein, mouse
  • NF-KappaB Inhibitor alpha
  • DYNLL1 protein, human
  • Cytoplasmic Dyneins