Chronic kidney disease (CKD) results in dramatic cortical porosity, a unique and devasting form of bone loss, which is associated with high fracture rates leading to increased hospitalization and mortality in patients. The cellular drivers of CKD-induced cortical porosity remain unexplored. Concurrent with declines in kidney function are disruptions in mineral metabolism often leading to chronically high parathyroid hormone (PTH) which has been associated with elevated bone porosity. The goal of this training proposal is to test the global hypothesis that chronic elevations in PTH affects osteocytes (lifespan and secretion of osteoclastic mediators) to promote porosity.
We aim to test this hypothesis using tissues from two animal models of CKD, human bone biopsy samples, and in vitro cultures of bone.
In Aim 1, we will quantify osteocyte apoptosis and RANKL across various disease stages in CKD rodents and human bone biopsies and relate these changes with cortical porosity and serum PTH.
In Aim 2, we will suppress PTH with etelcalcitide, a calcium sensing receptor agonist, and note the effects on porosity, osteocyte apoptosis, and RANKL. This will be done in both animals and in humans. Finally, utilizing rat bone primary cultures, we will administer CKD serum with and without a PTH-blocker as well as PTH alone to examine the direct/indirect effects of PTH in the setting of CKD on osteocyte RANKL and apoptosis. Together this combination of basic, translational, and clinical studies will enhance our knowledge of the drivers of cortical porosity in CKD and address the mechanisms of current therapeutic targets to improve bone health in patients with CKD. In addition, it presents an ideal training environment to enhance the applicant?s skills in basic, translational, and clinical work.
Patients with chronic kidney disease have chronically high serum parathyroid hormone (PTH) and cortical porosity which leads to increased fracture incidence and fracture-related complications including increased mortality. This study examines the associations between serum PTH and osteocytes, cells embedded within the cortical bone matrix, and correlates these alterations with cortical porosity. Additionally, this study will examine the impact of a therapeutic to suppress PTH on osteocytes and cortical porosity.
