title: Interactomics profiling of the negative regulatory function of carbon monoxide on RANKL-treated RAW 264.7 cells during osteoclastogenesis.
abstract: BACKGROUND
  During osteoclastogenesis, the maturation of osteoclast (OC) progenitors is stimulated by the receptor activator of nuclear factor-κB ligand (RANKL). Excess OC production plays a critical role in the pathogenesis of inflammatory bone disorders. Conversely, the inhibition of abnormal OC proliferation reduces inflammation-induced bone loss. Low concentrations of carbon monoxide (CO) are known to decrease inflammation and OC-mediated bone erosion but the molecular mechanism is unknown.
  
  
  RESULTS
  To obtain insight into the biological function of CO, cultured RANKL-treated RAW 264.7 cells were used in an in vitro experimental model of osteoclastogenesis. The results showed that CO inhibited: 1) tartrate-resistant acid phosphatase (TRAP)-positive cell formation; 2) F-actin ring production; 3) c-fos pathway activation; 4) the expression of cathepsin K, TRAP, calcitonin receptor, and matrix metalloproteinase-9 mRNAs; 5) the expression of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 in translation. Protein-protein interaction analysis predicted mitogen-activated protein kinase kinase kinase 4 as the controlling hub.
  
  
  CONCLUSIONS
  Low-concentrations of CO (250 ppm) may inhibit osteoclastogenesis. Data from STRING- and IPA-based interactome analyses suggested that the expression of proteins with the functions of signal transduction, enzymes, and epigenetic regulation are significantly altered by CO during RANKL-induced osteoclastogenesis. Our study provides the first interactome analysis of osteoclastogenesis, the results of which supported the negative regulation of OC differentiation by CO.
authors.forename: Feng-Jen
authors.initials: FJ
authors.lastname: Tseng
authors.forename: Wei-Tso
authors.initials: WT
authors.lastname: Chia
authors.forename: Jia-Fwu
authors.initials: JF
authors.lastname: Shyu
authors.forename: Guo-Hau
authors.initials: GH
authors.lastname: Gou
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.forename: Ching-Wu
authors.initials: CW
authors.lastname: Hsia
authors.forename: Min-Jen
authors.initials: MJ
authors.lastname: Tseng
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Neihu 114, Taipei, Taiwan, Republic of China. pan1628@yahoo.com.
authors.forename: Ru-Yu
authors.initials: RY
authors.lastname: Pan
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000199:Actins; D053245:RANK Ligand; D002248:Carbon Monoxide