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
differentiation
and bone formation. This 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. 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 morhogenetic proteins 2
and 4
(BMP-2/4). BMP-2/4 expression in the
vasculature stimulates
expression of osteoblastic transcription factors
including
MSX2 and RUNX2. In CKD, hyperphosphatemia
stimulates
expression of osterix completing the RUNX2 and
MSX2 induced
osteoblast transcriptome and inducing vascular
mineralization. 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
mineralization, 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
(Mathew,S et al,
Eur.J.Clin.Invest., 2006). Recently, the
laboratory has
been involved with the question of whether BMP-7
is a useful
new therapeutic agent for chronic kidney
disease. 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; see
figure).
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)
SCHOOL OF MEDICINE
