Holey Bones ” : How osteocytes might cause the development of cortical bone porosity

Cortical bone becomes porous in the elderly leading to skeletal fragility. Cortical porosity must be due to excessive osteoclastic bone resorption, but the underlying pathophysiology has not been established. It is now known that osteocytes buried within the bone matrix are an important source of the pro-osteoclastogenic cytokine RANKL, and that apoptotic osteocytes stimulate the synthesis of RANKL by viable neighboring osteocytes. In view of evidence that osteocyte apoptosis increases with advancing age, we measured cortical porosity in mice with osteocytes that are resistant to apoptosis due to deletion of Bak and Bax – two proteins essential for apoptotic death. Femoral cortical porosity in aged (21-22 month old) Bak/Baxdeficient mice was dramatically increased, as compared to aged wild type mice, and was associated with increased expression of RANKL by cortical osteocytes. The cortical pores contained osteoclasts and bone-forming osteoblasts, as well as blood vessels that deliver osteoclast and osteoblast progenitors into the pores. Consistent with the latter, cortical osteocytes of Bak/Bax-deficient mice also exhibited increased expression of the pro-angiogenic cytokine VEGF. Preliminary studies suggested that the synthesis of RANKL and VEGF by osteocytes is enhanced with advancing age by activation of the unfolded protein response to endoplasmic reticulum stress – a response that normally protects cells against noxious conditions such as hypoxia and oxidative stress. We propose that the development of cortical porosity with advancing age is due to excessive RANKL and VEGF production by damaged osteocytes, and that the increased porosity of aged Bak/Bax-deficient mice is due to exaggeration of the normal effect of aging on osteocyte function due to artificial prolongation of the life span of damaged osteocytes. A focus on Bone Health