title: Calcineurin/nuclear factor of activated T cells (NFAT) signaling in cobalt-chromium-molybdenum (CoCrMo) particles-induced tumor necrosis factor-α (TNFα) secretion in MLO-Y4 osteocytes.
abstract: Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment.
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, 600 South Paulina Street AF507, Chicago, Illinois 60612, USA.
authors.forename: Vbenosawemwinghaye
authors.initials: V
authors.lastname: Orhue
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanaji
authors.forename: Marco S
authors.initials: MS
authors.lastname: Caicedo
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Virdi
authors.forename: Dale R
authors.initials: DR
authors.lastname: Sumner
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Hallab
authors.forename: Holger
authors.initials: H
authors.lastname: Jahr
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sena
mesh_terms: D019644:Arthroplasty, Replacement, Hip; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008422:Materials Testing; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011475:Prosthesis Failure; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014800:Vitallium / Q000494:pharmacology*
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014800:Vitallium; D019703:Calcineurin