Interaction of PTH and Muscle Fndc5/Irisin in Renal Osteodystrophy

PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) affects nearly 1 in 7 people and leads to a 5-fold increased risk of fracture as compared with normal individuals. Disease progression leads to changes in bone and mineral metabolism, including prolonged elevations in parathyroid hormone (PTH), resulting in bone resorption. Despite clinical efforts to control PTH-induced bone loss, fracture risk in CKD patients has not changed. This indicates additional mechanisms are at play. We hypothesize a role may be played by myokines-- compounds produced by muscle-- that act on bone, including irisin. Irisin has been shown in healthy animal models to upregulate bone formation transcription factors and improve cortical bone mass. Our preliminary data suggests that the high PTH in CKD-MBD inhibits the positive effects of irisin and/or its precursor (Fndc5) on bone. We will test our hypothesis by 1) investigating the mechanism of this relationship in vivo in a CKD-mineral bone disorder (MBD) rat model and in vitro using cultured osteocytes and 2) validating this relationship in humans using muscle and bone biopsies from patients with CKD. This interplay may be a missing link to explain alterations in bone remodeling, offering a new therapeutic strategy for patients with CKD-MBD.