p63 Regulates Chondrocyte Survival in Articular Cartilage.

Objective p63, a transcription factor of the p53 family, regulates cell proliferation, survival, and apoptosis in various cells and tissues. Here, we examined expression and roles of p63 transcript variants in the growth plate and articular chondrocytes. Methods For in vivo analyses, we generated Cre-mediated transgenic mice of TAp63α and TAp63γ. To induce tissue-specific overexpression or deletion in chondrocytes, chondroprogenitor cells, or early limb bud mesenchymal cells, we used Col2a1-Cre, Sox9-Cre and Prx1-Cre mice, respectively. We analyzed osteoarthritis development with aging or surgically induced instability in Prx1-Cre;p63 mice. Results Among major variants, TAp63α and TAp63γ are highly expressed in mouse primary costal and articular chondrocytes. p63 protein was predominantly localized in the hypertrophic zone of the embryonic limb cartilage, and in the middle zone of articular cartilage. No obvious change was observed in skeletal growth of TAp63α transgenic mice, Sox9-Cre;p63 or Prx1-Cre;p63 mice, while that of TAp63γ transgenic mice was impaired due to ectopic apoptosis and the ensuing decreased number of chondrocytes. Expression of pro-apoptotic genes including Bax, Noxa, Puma, and Fas was increased in TAp63γ transgenic chondrocytes, and their transcription was probably sustained by p53 in p63 conditional knockout chondrocytes because both proteins were co-expressed in the growth plate. In contrast, p53 was expressed in the superficial zone of articular cartilage, differently from p63. Notably, Prx1-Cre;p63 mice showed significant resistance to osteoarthritis development, with suppression of chondrocyte apoptosis in the aging and surgical models. Conclusions We demonstrated regulation of chondrocyte survival in articular cartilage by p63. This article is protected by copyright. All rights reserved.