Abstract
Depletion of tumor protein p63 results in severe epithelial as well as limb defects in mice, suggesting that p63 is also required for endochondral ossification during long bone development. A key stage in endochondral ossification is chondrocyte hypertrophy, which has been associated with elevated levels of the p63 variant TAp63γ. To investigate the role of TAp63γ in chondrocyte differentiation and maturation, we developed stable TAp63γ expressing ATDC5 cells. Compared to control cells, TAp63γ cells showed significant upregulation of Col10a1 after 4 and 7 days in culture. Moreover, alkaline phosphatase, Alizarin red, and Alcian blue staining were stronger in TAp63γ cells, suggesting that TAp63γ promotes chondrocyte proliferation, hypertrophic differentiation, and possibly matrix mineralization. To investigate the in vivo function of TAp63γ during endochondral bone formation, we established transgenic mice that express flag-tagged TAp63γ driven by Col10a1 regulatory elements. Skeletal staining of transgenic mice at postnatal day 1 showed accelerated ossification in long bone, tail, and digit bones compared to wild-type littermates. Furthermore, Sox9 expression was reduced and Runx2 expression was increased in the proliferative and/or hypertrophic zones of these mice. Altogether, these results suggest that TAp63γ promotes endochondral ossification and skeletal development, at least partially via controlling chondrocyte differentiation and maturation.
Highlights
Tumor protein p63 is a member of the p53 tumor suppressor family and plays a role in ectoderm differentiation and in the basal regenerative layers of epithelial tissues in the adult [1]. p63 is important for formation of the limb bud which is developed from the mesoderm
Pathogenic P63 mutations are associated with four syndromes: ankyloblepharon-ectodermal defectscleft lip/palate syndrome (AEC), acro-dermato-unguallacrimal-tooth syndrome (ADULT), limb mammary www.aging-us.com syndrome (LMS), and Rapp-Hodgkin syndrome (RHS) [9]
P63 has been implicated a role in bone development for nearly two decades, little effort has been given to increasing our understanding of the detailed mechanism of p63 action
Summary
Tumor protein p63 is a member of the p53 tumor suppressor family and plays a role in ectoderm differentiation and in the basal regenerative layers of epithelial tissues in the adult [1]. p63 is important for formation of the limb bud which is developed from the mesoderm. Tumor protein p63 is a member of the p53 tumor suppressor family and plays a role in ectoderm differentiation and in the basal regenerative layers of epithelial tissues in the adult [1]. Knockout of p63 in mice results in defects in limb, craniofacial, and epithelial development. Specific defects include absent or truncated limbs and lack of epithelial tissues and their derivatives, including mammary, lachrymal, and salivary glands, due to loss of ectodermal stem cells [2,3,4]. Heterozygous missense mutations of the P63 gene in humans are closely related to ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome [7, 8]. Pathogenic P63 mutations are associated with four syndromes: ankyloblepharon-ectodermal defectscleft lip/palate syndrome (AEC), acro-dermato-unguallacrimal-tooth syndrome (ADULT), limb mammary www.aging-us.com syndrome (LMS), and Rapp-Hodgkin syndrome (RHS) [9]. Upregulation of p63 in the cartilage tissues of OA patients inhibits chondrocyte autophagy and contributes to OA progression [14], suggesting a role of p63 during articular cartilage degeneration
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