Interaction of PTH and muscle FNDC5/irisin in renal osteodystrophy

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Indiana University Indianapolis (Trustees of Indiana University) $104,433 on January 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the interaction between parathyroid hormone and muscle-derived irisin in chronic kidney disease–mineral bone disorder.

The research examines mechanisms by which elevated parathyroid hormone in kidney disease patients may inhibit the bone-protective effects of irisin and its precursor FNDC5. The recipient will conduct in vivo studies in a chronic kidney disease rat model and in vitro investigations using cultured osteocytes, then validate findings in humans through muscle and bone biopsies from chronic kidney disease patients. The work aims to identify a previously unexplained pathway in bone remodeling that could lead to new therapeutic strategies for fracture prevention in this population.

Performance occurs in Indianapolis, Indiana, with work extending from January 1, 2026, through July 31, 2028.

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.