BoneKEy-Osteovision | Commentary
Age-related bone loss: The cost of p53-mediated tumor suppression?
Robert L Jilka
DOI:10.1138/2002024
The skeleton becomes increasingly fragile with age. The pathogenetic mechanisms responsible are an increase in the production of osteoclasts or decrease in the production of osteoblasts, or an imbalance in the life span between these two cells (). Mesenchymal stem cells are the reservoir of osteoblasts in the bone marrow. Normally, stem cell number is maintained at a constant level because of their ability to produce an identical daughter stem cell, as well as a more differentiated progenitor (). A key function of the mesenchymal stem cell is to provide a sufficient number of osteoblasts to achieve complete refilling of the resorption cavity. During aging, there is a decline in the number of osteoblasts recruited to sites of bone remodeling (), perhaps due in part to a reduction in the number of mesenchymal stem cells ().
Telomere shortening, loss of sensitivity to, or production of, growth factors, and the cumulative effects of oxidative stress and DNA damage on cell function have been identified as factors contributing to loss of stem cells during aging, but the molecular link has remained elusive (). A fresh perspective on this problem is provided by the recent report of Tyner, Venkatachalam and colleagues in Nature () demonstrating that increased p53-mediated tumor suppression in mice causes a reduction in lifespan, and early degeneration of several organs, including the skeleton, perhaps through depletion of the relevant stem cells.
The p53 tumor suppressor is a 393 amino acid protein. It comprises an amino-terminal acidic transactivation domain, followed by an SH3 binding domain, a DNA binding domain, an oligomerization domain, and a C-terminal negative regulatory domain (). The protein is normally latent, and present at very low levels in the cell due to proteolysis. Stress, DNA damage, or inappropriate oncogene expression activate p53 by phosphorylation or acetylation of key amino acids in the transactivation domain and in the negative regulatory domain. These modifications increase the level of p53 by preventing its degradation, and they also promote oligomerization. Activated p53 binds to DNA and stimulates the transcription of genes like p21 that prevent replication, or genes such as bax that stimulate apoptosis, depending on the nature of the activation stimulus and cell type. Activated p53 also binds to a number of key proteins involved in the regulation of recombination, cell cycling and apoptosis. In this way, damaged cells, and cells that are potentially tumorigenic, cannot develop further.
The mouse made by Tyner et al. expresses a C-terminal fragment of p53 containing only the oligomerization and negative regulatory domains (). The fragment by itself does not trigger tumor suppression pathways, but when expressed in the presence of wild type p53 (in p53+/m mice) it enhances p53 function. As expected, p53+/m mice are highly resistant to tumor development. Remarkably however they also have a 23% reduction in life span and exhibit signs of premature aging such as lordokyphosis, organ atrophy, and a reduction in stress tolerance.
Early onset osteopenia in p53+/m mice was not directly measured, but may be inferred from the appearance of lordokyphosis, an indication of vertebral bone fragility that is commonly seen in very old mice. Consistent with bone loss, X-rays of p53+/m mice revealed a generalized decrease in bone mass; and histological examination of the proximal tibia showed a decrease in cortical thickness and absence of trabecular bone. Further strengthening the role of p53 in aging, transgenic mice overexpressing a different mutant form of p53 called pL53 also exhibit signs of progeria, including diminished bone mass, that was associated with tumor suppression ().
The authors propose that the reduced life span and early aging phenotype of their mice is the result of a p53-mediated depletion of stem cells; but several caveats should be noted. First, although transcripts corresponding to the C-terminal p53 fragment are expressed in p53+/m mice, the presence of the corresponding protein was not demonstrated. Second, more detailed studies are needed at the cell and tissue level to show that the skeletal phenotype of p53+/m and pL53 mice is similar to that seen in old mice. Finally, a stem cell defect in p53+/m and pL53 mice remains to be demonstrated. In particular, marrow of these mice should exhibit a reduction in mesenchymal stem cells associated with a reduction in bone formation and bone loss.
If overactive p53 accelerates aging and causes osteoporosis, loss of p53 should have the opposite effect. Unfortunately, aging per se cannot be studied in p53 null mice because they die in less than one year from tumors. However, Sakai et al. recently reported in the Journal of Bone and Mineral Research () that p53 null mice fail to lose bone following mechanical unloading due to hindlimb suspension. After one week of hindlimb suspension of normal mice, they observed a decreased in bone formation rate, a reduction in the number of mesenchymal stem cells, and increased p53 levels. In contrast, p53 null mice exhibited no significant change in bone or bone cell activity following hindlimb suspension. Moreover, p53 null mice had 2-fold more mesenchymal stem cells under basal conditions and their number was unaffected by mechanical unloading. It is thus conceivable that the decrease in mesenchymal stem cells in hindlimb unloaded normal mice may be due to p53-mediated apoptosis or suppression of replication, which could contribute to the development of osteopenia. The reason for increased p53 in hindlimb unloading remains to be established.
In summary, the work of Tyner et al. points to a role for p53 activation in the deleterious effects of age on several organs including the skeleton; and the JBMR report of Sakai et al. provides additional evidence for a link between p53 and osteogenesis. Clearly, additional work is needed to elucidate the control of p53 activation and its target genes in bone cells, and the impact of p53 activation on mesenchymal stem cell replication and survival.
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