Hruska Lab
Our laboratory has a strong tradition of discovery in the pathophysiologic mechanisms of renal injury, chronic kidney disease and its complications, renal osteodystrophy and vascular calcification. We have discovered that renal injury and chronic kidney disease directly impair skeletal anabolism by decreasing osteoblast and vascular smooth mucle cell differentiation. The consequent effect of loss of osteoblast function, decreased bone formation, is not associated with an equal inhibiton of bone resorption.
As a result, renal osteodystrophy contributes to the serum phosphorus levels in chronic kidney disease through excess osteoclast activity. Furthermore, we have shown that hyperphosphatemia is a direct stimulus to activation of a heterotopic osteogenic program in the vasculature. This program is activated in atherosclerosis by loss of repression of the bone morphogenetic proteins 2 and 4 (BMP-2/4) and osteoprogenitor transcription factors including Msx2. BMP-2/4 expression in the atherosclerotic vasculature stimulates expression of osteoblastic transcription factors including RUNX2. When atherosclerosis is complicated by CKD, hyperphosphatemia stimulates expression of osterix completing the RUNX2 and Msx2 induced osteoblast transcriptome and inducing vascular mineralization (see figure). The mechanism of hyperphosphatemia action is direct stimulation of signal transduction in the vascular cells expressing the osteoblastic phenotype.
Thus, in chronic kidney disease, we have discovered that the serum phosphorus is a cardiovascular risk factor. Correcting hyperphosphatemia causes loss of vascular calcium accumulation (Mathew,S et al JASN, 2007). Current studies are designed to assess the role of osterix in stimulation of vascular calcification, the role of the vascular smooth muscle transcription factors,and the importance of phosphorus as a risk factor in human cardiovascular disease. The actions of hyperphosphatemia are inhibited by BMP-7. The mechanisms of BMP-7 action in vascular calcification, renal osteodystrophy,and as a novel new renal therapeutic are active investigations in the laboratory (Hruska et al, Kid. Int., 2008).
Recently, the laboratory has been involved with the question of whether BMP-7 is a useful new therapeutic agent for chronic kidney disease (Mathew et al Eur. J. Clin Invest., 2006). BMP-7, an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct and glomerular podocyte. It activates receptors in the collecting duct, distal nephron, proximal tubule and podocytes. BMP-7 is therapeutic in tubulointerstitial nephritis and diabetic nephropathy (DePetris et al,Neph Dial Trans 2007 and Wang et al, Kid Int,2003). The actions of BMP-7 therapy include opposing the pathologic reactivation of the WNT pathway in tubulointerstitial nephritis through loss of the sFRP4 inhibitor (Surendran et al JASN, 2005), and inhibition of osteoblastic differentiation in the vasculature thereby decreasing vascular calcification (see figure).
Stimulation of vascular calcification by Chronic Kidney Disease (CKD) in mice with the metabolic syndrome (low density lipoprotein receptor deficient (LDLR-/-) fed high fat diets) and treatment with BMP-7. Panels A, B, and C are sections of the proximal aorta demonstrating large calcified atherosclerotic plaques in the LDLR-/- high fat fed mice. A) Large lipid laden plaque (between arrows) in proximal aorta of a sham-operated high fat fed LDLR-/- mouse. Thick arrows identify focal calcifications in the base of the plaque. (B) A large calcified plaque (between arrows) in the proximal aorta of a CKD high fat fed LDLR-/- mouse. (C) A large lipid laden plaque (between arrows) in the proximal aorta of a BMP-7 treated CKD high fat fed LDLR-/- mouse. The stain is alizarin red. Magnification is 400x in A-C.
Contact Information
Keith A. Hruska, M.D.
Professor of Pediatrics, Medicine, Cell Biology
Department of Pediatrics
5th Fl MPRB
Campus Box 8208
660 S. Euclid Avenue
St. Louis, MO 63110
(314) 286-2772
(314) 286-2894 (fax)
hruska_k@wustl.edu
Hruska Lab
Our laboratory has a strong tradition of discovery in the pathophysiologic mechanisms of renal injury, chronic kidney disease and its complications, renal osteodystrophy and vascular calcification. We have discovered that renal injury and chronic kidney disease directly impair skeletal anabolism by decreasing osteoblast and vascular smooth mucle cell differentiation. The consequent effect of loss of osteoblast function, decreased bone formation, is not associated with an equal inhibiton of bone resorption.
As a result, renal osteodystrophy contributes to the serum phosphorus levels in chronic kidney disease through excess osteoclast activity. Furthermore, we have shown that hyperphosphatemia is a direct stimulus to activation of a heterotopic osteogenic program in the vasculature. This program is activated in atherosclerosis by loss of repression of the bone morphogenetic proteins 2 and 4 (BMP-2/4) and osteoprogenitor transcription factors including Msx2. BMP-2/4 expression in the atherosclerotic vasculature stimulates expression of osteoblastic transcription factors including RUNX2. When atherosclerosis is complicated by CKD, hyperphosphatemia stimulates expression of osterix completing the RUNX2 and Msx2 induced osteoblast transcriptome and inducing vascular mineralization (see figure). The mechanism of hyperphosphatemia action is direct stimulation of signal transduction in the vascular cells expressing the osteoblastic phenotype.
Thus, in chronic kidney disease, we have discovered that the serum phosphorus is a cardiovascular risk factor. Correcting hyperphosphatemia causes loss of vascular calcium accumulation (Mathew,S et al JASN, 2007). Current studies are designed to assess the role of osterix in stimulation of vascular calcification, the role of the vascular smooth muscle transcription factors,and the importance of phosphorus as a risk factor in human cardiovascular disease. The actions of hyperphosphatemia are inhibited by BMP-7. The mechanisms of BMP-7 action in vascular calcification, renal osteodystrophy,and as a novel new renal therapeutic are active investigations in the laboratory (Hruska et al, Kid. Int., 2008).
Recently, the laboratory has been involved with the question of whether BMP-7 is a useful new therapeutic agent for chronic kidney disease (Mathew et al Eur. J. Clin Invest., 2006). BMP-7, an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct and glomerular podocyte. It activates receptors in the collecting duct, distal nephron, proximal tubule and podocytes. BMP-7 is therapeutic in tubulointerstitial nephritis and diabetic nephropathy (DePetris et al,Neph Dial Trans 2007 and Wang et al, Kid Int,2003). The actions of BMP-7 therapy include opposing the pathologic reactivation of the WNT pathway in tubulointerstitial nephritis through loss of the sFRP4 inhibitor (Surendran et al JASN, 2005), and inhibition of osteoblastic differentiation in the vasculature thereby decreasing vascular calcification (see figure).
Stimulation of vascular calcification by Chronic Kidney Disease (CKD) in mice with the metabolic syndrome (low density lipoprotein receptor deficient (LDLR-/-) fed high fat diets) and treatment with BMP-7. Panels A, B, and C are sections of the proximal aorta demonstrating large calcified atherosclerotic plaques in the LDLR-/- high fat fed mice. A) Large lipid laden plaque (between arrows) in proximal aorta of a sham-operated high fat fed LDLR-/- mouse. Thick arrows identify focal calcifications in the base of the plaque. (B) A large calcified plaque (between arrows) in the proximal aorta of a CKD high fat fed LDLR-/- mouse. (C) A large lipid laden plaque (between arrows) in the proximal aorta of a BMP-7 treated CKD high fat fed LDLR-/- mouse. The stain is alizarin red. Magnification is 400x in A-C.
Contact Information
Keith A. Hruska, M.D.
Professor of Pediatrics, Medicine, Cell Biology
Department of Pediatrics
5th Fl MPRB
Campus Box 8208
660 S. Euclid Avenue
St. Louis, MO 63110
(314) 286-2772
(314) 286-2894 (fax)
hruska_k@wustl.edu