Bovine lactoferricin induces TIMP-3 via the ERK1/2-Sp1 axis in human articular chondrocytes

Dongyao Yan, Di Chen, John R. Hawse, Andre J. van Wijnen, Hee Jeong Im

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Bovine lactoferricin (LfcinB) is a heparan sulfate-binding peptide with multiple bioactivities. In human articular cartilage, LfcinB antagonizes interleukin-1 β (IL-1β) and fibroblast growth factor 2 (FGF-2) in proteoglycan metabolism, catabolic protease expression, and induction of pro-inflammatory mediators. LfcinB specifically activates ERK1/2, p38 and Akt, but whether these signaling pathways control the expression of LfcinB target genes remained unknown. In this report, we characterized a novel aspect of LfcinB-mediated genetic response in human articular chondrocytes, tissue inhibitor of metalloproteinase 3 (TIMP-3) induction. Inhibition of individual signaling pathways revealed that ERK1/2 functions as the major pathway in TIMP-3 expression, whereas Akt plays a minor role. Further investigation identified Sp1 as a critical transcriptional activator in TIMP-3 regulation, and Sp1 activity is modulated by ERK1/2, not Akt. Comparative quantification indicates that significant downregulation of TIMP-3 occurs in OA chondrocytes, suggesting a beneficial role of LfcinB in OA pathogenesis. Our results collectively provide new insights into the mechanism of action of LfcinB, and support the candidacy of LfcinB as a chondroprotective agent.

Original languageEnglish (US)
Pages (from-to)12-18
Number of pages7
JournalGene
Volume517
Issue number1
DOIs
StatePublished - Mar 15 2013

Keywords

  • Articular cartilage
  • Bovine lactoferricin
  • Chondrocyte
  • Osteoarthritis
  • Tissue inhibitor of metalloproteinase

ASJC Scopus subject areas

  • Genetics

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