p53 control of bone remodeling.

Tumor suppressor p53 is a transcription regulator that displays anti-proliferation activities once activated by stress, in particular genotoxic stress. Recent mouse genetic studies revealed a critical role for p53 in bone remodeling, supported by both loss-of-function and gain-of function studies. p53 deficiency concurrently enhances proliferation and accelerates differentiation in mesenchymal stem cells and osteoprogenitor cells, resulting in an increase in bone formation and bone mass/density. Moreover, Atm, c-Abl, and Mdm2, upstream regulators of p53 in DNA damage response, regulate osteoblast differentiation and bone remodeling as well. While the molecular mechanisms await further investigation, there is evidence to suggest that p53 regulate osteoblast differentiation via transcription factors Runx2/Osterix, which are involved in osteoblast differentiation and transformation and are under the control of BMP and IGF pathways. Moreover, there are studies showing that p53 inhibits cell differentiation in many other tissues. These findings suggest that p53 acts as a safeguard of differentiation in addition to "guardian of the genome" and challenge the conventional wisdom that tumor suppressors usually block cell proliferation and promote differentiation.