title: Lactoferricin mediates anabolic and anti-catabolic effects in the intervertebral disc.
abstract: Lactoferricin (LfcinB) antagonizes biological effects mediated by angiogenic and catabolic growth factors, in addition to pro-inflammatory cytokines and chemokines in human endothelial cells and tumor cells. However, the effect of LfcinB on intervertebral disc (IVD) cell metabolism has not yet been investigated. Using bovine nucleus pulposus (NP) cells, we analyzed the effect of LfcinB on proteoglycan (PG) accumulation, PG synthesis, and anabolic gene expression. We assessed expression of genes for matrix-degrading enzymes such as matrix metalloproteases (MMPs) and a disintegrin-like and metalloprotease with thrombospondin motifs (ADAMTS family), as well as their endogenous inhibitors, tissue inhibitor of metalloproteases (TIMPs). In order to understand the specific molecular mechanisms by which LfcinB exerts its biological effects, we investigated intracellular signaling pathways in NP cells. LfcinB increased PG accumulation mainly via PG synthesis in a dose-dependent manner. Simultaneously, LfcinB dose-dependently downregulated catabolic enzymes. LfcinB's anti-catabolic effects were further demonstrated by a dose-dependent increase in multiple TIMP family members. Our results demonstrate that ERK and/or p38 mitogen-activated protein kinase pathways are the key signaling cascades that exert the biological effects of LfcinB in NP cells, regulating transcription of aggrecan, SOX-9, TIMP-1, TIMP-2, TIMP-3, and iNOS. Our results suggest that LfcinB has anabolic and potent anti-catabolic biological effects on bovine IVD cells that may have considerable promise in the treatment of disc degeneration in the future.
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ellman
authors.forename: Howard S
authors.initials: HS
authors.lastname: An
authors.forename: Dongyao
authors.initials: D
authors.lastname: Yan
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007403:Intervertebral Disc / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy; D007781:Lactoferrin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018384:Oxidative Stress; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D019714:Tissue Inhibitor of Metalloproteinases; C082171:lactoferricin B; D007781:Lactoferrin; D051722:ADAM Proteins