Effects of kidney disease on the regulation of the skeletal hormone FGF23
Fibroblast growth factor (FGF) 23 is a phosphate and vitamin D regulating hormone produced by bone. In chronic kidney disease (CKD), bone and mineral metabolism is altered, and FGF23 levels are highly increased. Increased FGF23 in CKD is associated with cardiovascular mortality. In our lab, we study the transcriptional and post-translational mechanisms of regulation of FGF23 with the goal to lower FGF23 levels and improve outcomes in CKD. We particularly focus on one factor, dentin matrix protein 1 (DMP1), an inhibitor of FGF23 produced by osteocytes. In mice with progressive CKD (Col4a3KO), we showed that DMP1 expression is reduced and lower DMP1 contributes to FGF23 excess. We also showed that genetic or pharmacologic DMP1 supplementation prevents FGF23 increase in mice with CKD, suggesting that DMP1 may represent a novel therapeutic molecule to improve outcomes in CKD. These studies are funded by NIH/NIDDK and are the central focus of a patent on amelioration of CKD.
Pathogenesis of renal osteodystrophy
Renal osteodystrophy is a bone disease that commonly occurs in patients with chronic kidney disease (CKD). It is characterized by alterations of bone morphology, bone material properties and bone cellular functions leading to impairment in bone strength and quality. As a result, patients with CKD have an increased risk of bone fractures that persists during dialysis and after kidney transplantation. In bone, the osteocyte is a terminally differentiated cell that coordinates activities of bone mineralization and bone remodeling. We have found that osteocyte morphology and function are altered in mice with CKD. In our lab, we use high resolution imaging (3D-microCT), bone histomorphometry, molecular and genomic analyses in vivo and in vitro, to understand the causes of osteocyte alterations and their contribution to the pathogenesis of renal osteodystrophy.
Role of FGF23 in CKD-associated cardiac hypertrophy
Chronic Kidney Disease (CKD) is associated with cardiovascular mortality. Enlargement of the left ventricle of the heart contributes to adverse cardiovascular events, and may be caused in part by increased levels of fibroblast growth factor (FGF) 23 in CKD. Our lab has shown that lowering FGF23 levels in mice with CKD is associated with improved heart morphology and lifespan. Using genetic models of FGF23 excess and FGF23 deletion, echocardiography, heart histology, molecular and genomic analyses in vivo and in vitro, we investigate FGF23-mediated organ crosstalk between the bone and the heart in health and disease states.