Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway

Noboru Taniguchi, Beatriz Caramés, Yasuhiko Kawakami, Brad A. Amendt, Setsuro Komiya, Martin Lotz

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis. Mechanisms that regulate the unique phenotype of SZ chondrocytes and maintain SZ integrity are unknown. We recently demonstrated that expression of the chromatin protein high mobility group box (HMGB) protein 2 is restricted to the SZ in articular cartilage suggesting a transcriptional regulation involving HMGB2 in SZ. Here, we show that an interaction between HMGB2 and the Wnt/β-catenin pathway regulates the maintenance of the SZ.Wefound that the Wnt/β-catenin pathway is active specifically in the SZ in normal mouse knee joints and colocalizes with HMGB2. Both Wnt signaling and HMGB2 expression decrease with aging in mouse joints. Our molecular studies show that HMGB2 enhances the binding of Lef-1 to its target sequence and potentiates transcriptional activation of the Lef-1-β-catenin complex. The HMG domain within HMGB2 is crucial for interaction with Lef-1, suggesting that both HMGB2 and HMGB1 may be involved in this function. Furthermore, conditional deletion of β-catenin in cultured mouse chondrocytes induced apoptosis. These findings define a pathway where protein interactions of HMGB2 and Lef-1 enhance Wnt signaling and promote SZ chondrocyte survival. Loss of the HMGB2-Wnt signaling interaction is a new mechanism in aging-related cartilage pathology.

Original languageEnglish (US)
Pages (from-to)16817-16822
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number39
DOIs
StatePublished - Sep 29 2009

Keywords

  • Aging
  • Apoptosis
  • Osteoarthritis
  • Superficial zone

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