Different consequences of cellular aging in cortical versus cancellous bone- Resubmission

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Project Summary/Abstract Aging is responsible for the majority of fractures in both women and men. The cellular changes in the skeleton of aged mice are similar to those observed in aged humans. In mice, trabecular bone loss is associated with low bone remodeling, while cortical thinning and porosity are associated with high bone remodeling. These findings suggest that different molecular mechanisms underlie the bone loss in these two compartments. Cellular senescence contributes to the functional decline of multiple tissues with age and DNA damage is a major cause of senescence. DNA damage causes senescence via activation of p53 and up-regulation of the cell cycle inhibitor p21 and/or p16. DNA damage also causes accumulation of the transcription factor GATA4, which promotes the senescence associated secretory phenotype (SASP). Systemic clearance of senescent cells delays several age- associated disorders and increases bone mass in old mice. We have shown that the number of osteoprogenitors in murine bone marrow declines with age and that these cells have increased markers of senescence. Cortical osteocytes also exhibit increased markers of senescence in aged mice and this is associated with elevated production of RANKL. Induction of senescence in bone organ cultures by DNA damage is sufficient to increase GATA4 and RANKL production. Moreover, overexpression of GATA4 in vitro is sufficient to increase RANKL and other components of the SASP. Administration of senolytics to old mice attenuates markers of senescence in osteoprogenitors and osteocytes. Notably, mice lacking RANKL in osteocytes are protected from the loss of cortical but not trabecular bone with age. We hypothesize that activation of p53/p21 in osteoprogenitors causes their senescence and thereby decreases osteoblast number and bone formation and that accumulation of senescent osteocytes in cortical, but not trabecular, bone increases RANKL and bone resorption via GATA4 stimulation. In Aim 1 we will determine whether DNA damage in osteoblast lineage cells is sufficient to induce senescence and reduce bone mass. To do this, we will generate mice with oxidative stress- induced senescence in either the entire osteoblast lineage or only in mature osteoblasts and osteocytes. Administration of the senolytic PZ15227 will reveal what components of the phenotype are due to senescence. In Aim 2 we will determine the contribution of the p53/p21 pathway in osteoprogenitors to skeletal aging by aging mice with p53 or p21 loss-of-function. In Aim 3 we will investigate the differential contribution of senescent osteocytes to increased bone resorption in trabecular versus cortical bone with age by aging mice with GATA4 loss-of-function in osteocytes. We will also quantify osteocyte senescence in cortical versus trabecular bone and determine whether senescent osteocytes express higher levels of RANKL. Successful completion of these studies should establish for the first time whether senescence of osteoprogenitors and osteocytes contributes to the loss of bone mass with age, and help clarify different aging mechanisms in cortical versus trabecular bone.