Regulation of the Catabolic Cascade in Osteoarthritis by the zinc-ZIP8-MTF1 Axis

Cell. 2014 Feb 13;156(4):730-43. doi: 10.1016/j.cell.2014.01.007.

Abstract

Osteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn(2+)-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • Aged
  • Animals
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Osteoarthritis / metabolism*
  • Osteoarthritis / pathology*
  • Signal Transduction*
  • Up-Regulation
  • Zinc / metabolism

Substances

  • Cation Transport Proteins
  • Kruppel-Like Transcription Factors
  • Mif1 protein, mouse
  • Slc39a8 protein, mouse
  • ADAM Proteins
  • Matrix Metalloproteinases
  • Zinc