The modulation of the oxidative stress response in chondrocytes by Wip1 and its effect on senescence and dedifferentiation during in vitro expansion

Byung Hyun Cha, Ji Seon Lee, Sung Won Kim, Hyuk Jin Cha, Soo Hong Lee

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Obtaining a sufficient number of cells ex vivo for tissue regeneration, which are appropriate for cartilage repair, requires improved techniques for the continuous expansion of chondrocytes in a manner that does not change their innate characteristics. Rapid senescence or dedifferentiation during in vitro expansion results in loss of chondrocyte phenotype and the formation of fibrous cartilage replacement tissue, rather than hyaluronic cartilage, after transplantation. As demonstrated in the current study, wild-type p53-inducible phosphatase (Wip1), a well-established stress modulator, was highly expressed in early-passage chondrocytes, but declined rapidly during in vitro expansion. Stable Wip1-expressing chondrocytes generated by microporation were less susceptible to the onset of senescence and dedifferentiation, and were more resistant to oxidative stress. The increased resistance of Wip1 chondrocytes to oxidative stress was due to modulation of p38 mitogen-activated protein kinase (MAPK) activity. Importantly, chondrocytes expressing Wip1 maintained their innate chondrogenic properties for a longer period of time, resulting in improvements in cartilage regeneration after transplantation. Chondrocytes from Wip1 knockout (Wip1-/-) mice were defective in cartilage regeneration compared with those from wild-type mice. Thus, Wip1 expression represents a potentially useful mechanism by which a chondrocyte phenotype can be retained during in vitro expansion through modulation of cellular stress responses.

Original languageEnglish
Pages (from-to)2380-2388
Number of pages9
JournalBiomaterials
Volume34
Issue number9
DOIs
StatePublished - Mar 2013

Keywords

  • Cartilage tissue development
  • Chondrocyte
  • Dedifferentiation
  • Oxidative stress modulator
  • Senescence
  • Wip-1

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