BMP-7 (OP-1) Kidney disorder articles

Posted: Tue Apr 04, 2006 10:06 am

1: Kidney Int. 2006 Jan;69(2):213-7.

Renal fibrosis: new insights into the pathogenesis and therapeutics.

Liu Y.

Division of Cellular and Molecular Pathology, Department of Pathology,
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
liuy@upmc.edu

Renal fibrosis is the inevitable consequence of an excessive accumulation of
extracellular matrix that occurs in virtually every type of chronic kidney
disease. The pathogenesis of renal fibrosis is a progressive process that
ultimately leads to end-stage renal failure, a devastating disorder that
requires dialysis or kidney transplantation. In a simplistic view, renal
fibrosis represents a failed wound-healing process of the kidney tissue after
chronic, sustained injury. Several cellular pathways, including mesangial and
fibroblast activation as well as tubular epithelial-mesenchymal transition, have
been identified as the major avenues for the generation of the matrix-producing
cells in diseased conditions. Among the many fibrogenic factors that regulate
renal fibrotic process, transforming growth factor-beta (TGF-beta) is one that
plays a central role. Although defective matrix degradation may contribute to
tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes
in the injured kidney have become increasingly complicated. Recent discoveries
on endogenous antifibrotic factors have evolved novel strategies aimed at
antagonizing the fibrogenic action of TGF-beta/Smad signaling. Many therapeutic
interventions appear effective in animal models; however, translation of these
promising results into humans in the clinical setting remains a daunting task.
This mini-review attempts to highlight the recent progress in our understanding
of the cellular and molecular pathways leading to renal fibrosis, and discusses
the challenges and opportunities in developing therapeutic strategies.

Publication Types:
Review

PMID: 16408108 [PubMed - indexed for MEDLINE]

2: J Clin Invest. 2006 Jan;116(1):70-9. Epub 2005 Dec 8.

Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist
expressed in the kidney, accelerates tubular injury.

Yanagita M, Okuda T, Endo S, Tanaka M, Takahashi K, Sugiyama F, Kunita S,
Takahashi S, Fukatsu A, Yanagisawa M, Kita T, Sakurai T.

COE Formation for Genomic Analysis of Disease Model Animals with Multiple
Genetic Alterations, Graduate School of Medicine, Kyoto University, Kyoto,
Japan. motoy@kuhp.kyoto-u.ac.jp

Dialysis dependency is one of the leading causes of morbidity and mortality in
the world, and once end-stage renal disease develops, it cannot be reversed by
currently available therapy. Although administration of large doses of bone
morphogenetic protein-7 (BMP-7) has been shown to repair established renal
injury and improve renal function, the pathophysiological role of endogenous
BMP-7 and regulatory mechanism of its activities remain elusive. Here we show
that the product of uterine sensitization-associated gene-1 (USAG1), a novel BMP
antagonist abundantly expressed in the kidney, is the central negative regulator
of BMP function in the kidney and that mice lacking USAG-1 (USAG1 mice) are
resistant to renal injury. USAG1 mice exhibited prolonged survival and preserved
renal function in acute and chronic renal injury models. Renal BMP signaling,
assessed by phosphorylation of Smad proteins, was significantly enhanced in
USAG1 mice with renal injury, indicating that the preservation of renal function
is attributable to enhancement of endogenous BMP signaling. Furthermore, the
administration of neutralizing antibody against BMP-7 abolished renoprotection
in USAG1 mice, indicating that USAG-1 plays a critical role in the modulation of
renoprotective action of BMP and that inhibition of USAG-1 is a promising means
of development of novel treatment for renal diseases.

PMID: 16341262 [PubMed - indexed for MEDLINE]

3: Kidney Int Suppl. 2005 Dec;(99):S142-51.

Connections between vascular calcification and progression of chronic kidney
disease: therapeutic alternatives.

Hruska KA, Mathew S, Davies MR, Lund RJ.

Washington University School of Medicine, Renal Division, Department of
Pediatrics, St. Louis, MO 63110, USA. hruska_k@wustl.edu

We have shown that renal injury and chronic kidney disease (CKD) directly
inhibit skeletal anabolism, and that stimulation of bone formation decreases the
serum phosphate. Most recently, these observations were rediscovered in
low-density lipoprotein receptor null mice fed high-fat/cholesterol diets, a
model of the metabolic syndrome (hypertension, obesity, dyslipidemia, and
insulin resistance). We had demonstrated that these mice have vascular
calcification (VC) of both the intimal atherosclerotic type and medial type. We
have shown that VC is worsened by CKD and ameliorated by bone morphogenetic
protein -7 (BMP-7). The finding that high-fat-fed low-density lipoprotein
receptor null animals without CKD have hyperphosphatemia led us to examine the
skeletons of these mice. We found significant reductions in bone formation
rates, associated with increased VC and superimposing CKD results in the
adynamic bone disorder (ABD), while VC was worsened and hyperphosphatemia
persisted. A pathological link between abnormal bone mineralization and VC
through the serum phosphorus was demonstrated by the partial effectiveness of
directly reducing the serum phosphate by a phosphate binder that had no skeletal
action. BMP-7 treatment corrected the ABD and corrected hyperphosphatemia,
compatible with BMP-7-driven stimulation of skeletal phosphate deposition
reducing plasma phosphate and thereby removing a major stimulus to VC. Thus, in
the metabolic syndrome with CKD, a reduction in bone-forming potential of
osteogenic cells leads to ABD producing hyperphosphatemia and VC, processes
ameliorated by the skeletal anabolic agent BMP-7, in part through increased bone
formation and skeletal deposition of phosphate, and in part through direct
actions on vascular smooth muscle cells. We have demonstrated that the processes
leading to vascular calcification begin with even mild levels of renal injury
before demonstrable hyperphosphatemia, and they are preventable and treatable.
Therefore, early intervention in CKD is warranted and may affect mortality of
the disease.

PMID: 16336568 [PubMed - indexed for MEDLINE]

4: Dev Biol. 2005 Oct 15;286(2):637-46. Epub 2005 Sep 8.

BMP4 substitutes for loss of BMP7 during kidney development.

Oxburgh L, Dudley AT, Godin RE, Koonce CH, Islam A, Anderson DC, Bikoff EK,
Robertson EJ.

Wellcome Trust Center for Human Genetics, University of Oxford, Roosevelt Drive,
Oxford, UK.

Functional inactivation of divergent bone morphogenetic proteins (BMPs) causes
discrete disturbances during mouse development. BMP4-deficient embryos display
mesodermal patterning defects at early post-implantation stages, whereas loss of
BMP7 selectively disrupts kidney and eye morphogenesis. Whether these distinct
phenotypes simply reflect differences in expression domains, or alternatively
intrinsic differences in the signaling properties of these ligands remains
unknown. To address this issue, we created embryos exclusively expressing BMP4
under control of the BMP7 locus. Surprisingly, this novel knock-in allele
efficiently rescues kidney development. These results demonstrate unequivocally
that these structurally divergent BMP family members, sharing only minimal
sequence similarity can function interchangeably to activate all the essential
signaling pathways for growth and morphogenesis of the kidney. Thus, we conclude
that partially overlapping expression patterns of BMPs serve to modulate
strength of BMP signaling rather than create discrete fields of ligands with
intrinsically different signaling properties.

PMID: 16154126 [PubMed - indexed for MEDLINE]

5: Nefrologia. 2005;25 Suppl 2:109-16.

[New therapeutic strategies in secondary hyperparathyroidism on dialysis (II):
vitamin D analogues and calcium-mimetics]

[Article in Spanish]

Bover J, Ballarin J, Andres E, Ortiz-Herbener F, Barcelo P.

Fundacio Puigvert, Universidad Autonoma de Barcelona UAB, Barcelona.

Secondary hyperparathyroidism (SHP) is a frequent complication of dialysis
patients. In this second article we will analyze the new vitamin D analogs,
capable of decreasing parathyroid hormone (PTH) levels with a lower effect on
intestinal calcium and phosphorus absorption. Among other advantages described
in the experimental setting, paricalcitol shows a survival benefit in dialysis
patients as compared to calcitriol, at least in retrospective studies, and thus
it became our first-line vitamin D derivative. Calcimimetics are unique since
they decrease PTH levels without increasing serum calcium and phosphorus.
Actually, calcium and phosphorus decrease in a significant number of patients.
These drugs will soon be authorized in Spain, and we describe the better
achievement of K/DOQI guidelines as well as other beneficial effects observed in
the experimental animal with them. Finally, we mention the potential benefit of
mild metabolic acidosis, the use of bisphosphonates, the role of bone
morphogenetic protein BMP-7, and the use of teriparatide. The future treatment
of SHP will probably require the independent management of calcium, phosphorus,
vitamin D and PTH. Thus, low-dose combined treatments with selective drugs may
prove more effective than sequential therapies.

Publication Types:
Review

PMID: 16050413 [PubMed - indexed for MEDLINE]

6: Circ Res. 2005 Jul 22;97(2):105-14.

Bone morphogenetic proteins in vascular calcification.

Hruska KA, Mathew S, Saab G.

Renal Division, Department of Pediatrics, Washington University School of
Medicine, St. Louis, MO, USA. hruska_k@kids.wustl.edu

Vascular calcification is a common problem among the elderly and those with
chronic kidney disease (CKD) and diabetes. The process of tunica media vascular
calcification in CKD appears to involve a phenotypic change in the vascular
smooth muscle cell (VSMC) resulting in cell-mediated mineralization of the
extracellular matrix. The bone morphogenetic proteins (BMPs) are important
regulators in orthotopic bone formation, and their localization at sites of
vascular calcification raises the question of their role. In this review, we
will discuss the actions of the BMPs in vascular calcification. Although the
role of BMP-2 in vascular calcification is not proven, it has been the most
studied member of the BMP family in this disease process. The role of BMP-2 may
be through inducing osteoblastic differentiation of VSMCs through induction of
MSX-2, or by inducing apoptosis of VSMCs, a process thought critical in the
initiation of vascular calcification. Additionally, BMP-2 may be related to loss
of regulation of the matrix Gla protein. A second BMP, BMP-7, less studied than
BMP-2 may have opposing actions in vascular calcification. In postnatal life,
BMP-7 is expressed primarily in the kidney, and expression is diminished by
renal injury. BMP-7 is an important regulator of skeletal remodeling and the
VSMC phenotype. BMP-7 restores skeletal anabolic balance in animal models of CKD
with disordered skeletal modeling, also reducing serum phosphate in the process.
BMP-7 also reverses vascular calcification in CKD, and reduction in vascular
calcification is due, in part, to reduced serum phosphate, an important inducer
of VSMC-mediated vascular mineralization and in part to direct actions on the
VSMC.

Publication Types:
Review

PMID: 16037577 [PubMed - indexed for MEDLINE]

7: Pediatr Nephrol. 2005 Sep;20(9):1230-6. Epub 2005 Jul 21.

Downregulation of the expression of bone morphogenetic protein 7 in experimental
pyelonephritis.

Biyikli NK, Tugtepe H, Cakalagaoglu F, Ilki A, Alpay H.

Department of Pediatric Nephrology, Marmara University School of Medicine,
Tophanelioglu cd No. 13-15, 81190 Altunizade, Istanbul, Turkey.
nesebiyikli@superonline.com

Bone morphogenetic protein 7 (BMP 7) is a member of the transforming growth
factor (TGF) beta superfamily and is involved in regeneration, repair, and
development of specific tissues, for example kidney, gut, lens, and skeleton.
BMP 7 has emerged as a renotrophic factor and experimental studies have shown
its protective role against fibrotic processes. Tubulointerstitial changes are
present in the pyelonephritic kidney which progresses to fibrosis. Renal
fibrosis may lead to significant morbidity in the form of hypertension,
proteinuria, and loss of renal function. The objective of this study was to
investigate BMP 7 expression in experimental acute and chronic pyelonephritis
models. Eighteen Wistar rats were injected with 0.1 mL solution containing E.
coli ATCC 25922 10(10) cfu mL(-1) into left renal medullae. Six rats were used
as a sham group and were given 0.1 mL 0.9% NaCl. Pyelonephritic rats were
sacrificed 24 h (group I, n=6), 1 week (group II, n=6), and 6 weeks (group III,
n=6) after E. coli injection. Serum creatinine levels were analyzed. Renal
tissues were studied histopathologically by use of hematoxylin and eosin and
scored for diagnosis of pyelonephritis. BMP 7 expression was studied
semiquantitatively by immunohistochemical staining. Acute (group I) and chronic
(group II and group III) pyelonephritic histopathological changes were observed
in experimental pyelonephritic groups. A gradual decrease in BMP 7 expression
was observed in the tubulointerstitial and tubular area of the pyelonephritic
kidneys, mildest in the acute pyelonephritic group and most severe in the
chronic pyelonephritic 6th week group. A statistically significant difference
was observed between tubulointerstitial BMP 7 expression by groups I and III
(P=0.017) and by groups III and IV (P=0.000). Tubular BMP 7 expression was
statistically significantly different between groups II and IV (P=0.009) and
between groups III and IV (P=0.002). The data imply that BMP 7 has a major role
in chronic pyelonephritis. Tubulointerstitial and tubular BMP 7 expression also
had a significant negative correlation with fibrosis, tubular, atrophy, and
vascular changes. Serum creatinine levels of the study group were all normal. We
conclude that the decrease in renal BMP 7 expression in experimental chronic
pyelonephritis is one of the factors responsible for fibrotic changes in
persistent renal damage.

PMID: 16034630 [PubMed - indexed for MEDLINE]

8: Clin Exp Nephrol. 2005 Jun;9(2):100-1.

Recapitulation of kidney development paradigms by BMP-7 reverses chronic renal
injury.

Okada H, Kalluri R.

Center for Matrix Biology, DANA 514, Beth Israel Deaconess Medical Center, 330
Brookline Avenue, Boston, MA 02215, USA.

Publication Types:
Review

PMID: 15980942 [PubMed - indexed for MEDLINE]

9: J Biol Chem. 2005 Jul 29;280(30):27970-80. Epub 2005 Jun 1.

The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix.

Gregory KE, Ono RN, Charbonneau NL, Kuo CL, Keene DR, Bachinger HP, Sakai LY.

Shriners Hospital for Children, Portland, Oregon 97239, USA.

Biochemical and biophysical methods are used to show that BMP-7 is secreted as a
stable complex consisting of the processed growth factor dimer noncovalently
associated with its two prodomain propeptide chains and that the BMP-7 complex
is structurally similar to the small transforming growth factor beta (TGFbeta)
complex. Because the prodomain of TGFbeta interacts with latent TGFbeta-binding
proteins, a family of molecules homologous to the fibrillins, the prodomain of
BMP-7 was tested for binding to fibrillin-1 or to LTBP-1. The BMP-7 prodomain
and BMP-7 complex, but not the separated growth factor dimer, interact with
N-terminal regions of fibrillin-1. This interaction may target the BMP-7 complex
to fibrillin microfibrils in the extracellular matrix. Immunolocalization of
BMP-7 in tissues like the kidney capsule and skin reveals co-localization with
fibrillin. However, BMP-7 immunolocalization in other tissues known to be active
sites for BMP-7 signaling is not apparent, suggesting that immunolocalization of
BMP-7 in certain tissues represents specific extracellular storage sites. These
studies suggest that the prodomains of TGFbeta-like growth factors are important
for positioning and concentrating growth factors in the extracellular matrix. In
addition, they raise the possibility that prodomains of other TGFbeta-like
growth factors interact with fibrillins and/or LTBPs and are also targeted to
the extracellular matrix.

PMID: 15929982 [PubMed - indexed for MEDLINE]

10: Cytokine Growth Factor Rev. 2005 Jun;16(3):299-308.

Bone morphogenetic proteins in development and homeostasis of kidney.

Simic P, Vukicevic S.

Laboratory for Mineralized Tissues, Department of Anatomy, School of Medicine,
University of Zagreb, Salata 11, 10 000 Zagreb, Croatia.

Bone morphogenetic proteins play a key role in kidney development and postnatal
function. The kidney has been identified as a major site of bone morphogenetic
protein (BMP)-7 synthesis during embryonic and postnatal development, which
mediates differentiation and maintenance of metanephric mesenchyme. Targeted
disruption of BMP-7 gene expression in mice resulted in dysgenic kidneys with
hydroureters, causing uremia within 24h after birth. Several experimental animal
models of acute and chronic renal injury have all unequivocally shown beneficial
effect of BMP-7 in ameliorating the severity of damage by preventing
inflammation and fibrosis. Apart from the beneficial effect on kidney disease
itself, BMP-7 improves important complications of chronic renal impairment such
as renal osteodystrophy and vascular calcification.

Publication Types:
Review

PMID: 15923134 [PubMed - in process]

11: Mol Cell Biol. 2005 May;25(9):3648-57.

Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal
epithelial cell morphogenesis.

Leung-Hagesteijn C, Hu MC, Mahendra AS, Hartwig S, Klamut HJ, Rosenblum ND,
Hannigan GE.

Cancer Research Program, Research Institute, Hospital for Sick Children, 555
University Ave., Toronto, Ontario M5G 1X8, Canada.

Bone morphogenetic protein 7 (BMP7) stimulates renal branching morphogenesis via
p38 mitogen-activated protein kinase (p38(MAPK)) and activating transcription
factor 2 (ATF-2) (M. C. Hu, D. Wasserman, S. Hartwig, and N. D. Rosenblum, J.
Biol. Chem. 279:12051-12059, 2004). Here, we demonstrate a novel role for
integrin-linked kinase (ILK) in mediating renal epithelial cell morphogenesis in
embryonic kidney explants and identify p38(MAPK) as a target of ILK signaling in
a cell culture model of renal epithelial morphogenesis. The spatial and temporal
expression of ILK in embryonic mouse kidney cells suggested a role in branching
morphogenesis. Adenovirus-mediated expression of ILK stimulated and expression
of a dominant negative ILK mutant inhibited ureteric bud branching in embryonic
mouse kidney explants. BMP7 increased ILK kinase activity in inner medullary
collecting duct 3 (IMCD-3) cells, and adenovirus-mediated expression of ILK
increased IMCD-3 cell morphogenesis in a three-dimensional culture model. In
contrast, treatment with a small molecule ILK inhibitor or expression of a
dominant negative-acting ILK (ILK(E359K)) inhibited epithelial cell
morphogenesis. Further, expression of ILK(E359K) abrogated BMP7-dependent
stimulation. To investigate the role of ILK in BMP7 signaling, we showed that
ILK overexpression increased basal and BMP7-induced levels of phospho-p38(MAPK)
and phospho-ATF-2. Consistent with its inhibitory effects on IMCD-3 cell
morphogenesis, expression of ILK(E359K) blocked BMP7-dependent increases in
phospho-p38(MAPK) and phospho-ATF-2. Inhibition of p38(MAPK) activity with the
specific inhibitor, SB203580, failed to inhibit BMP7-dependent stimulation of
ILK activity, suggesting that ILK functions upstream of p38(MAPK) during BMP7
signaling. We conclude that ILK functions in a BMP7/p38(MAPK)/ATF-2 signaling
pathway and stimulates epithelial cell morphogenesis.

PMID: 15831470 [PubMed - indexed for MEDLINE]

12: Curr Opin Investig Drugs. 2005 Mar;6(3):255-61.

Therapeutic targets for prevention and regression of progressive fibrosing renal
diseases.

Eitner F, Floege J.

Division of Nephrology and Immunology, Aachen University, Pauwelsstr 30, 52074
Aachen, Germany. feitner@ukaachen.de

Renal fibrosis complicates most chronic renal diseases, leading to a progressive
loss of function and ultimately resulting in terminal renal failure. Molecular
mechanisms underlying the development and progression of renal fibrosis have
been increasingly identified, and much progress has been made towards a better
understanding of the roles of different growth factors/cytokines and regulators
of matrix turnover, as well as of the interactions between renal inflammation
and fibrosis. This review focuses on recent advances in the identification of
novel targets, as well as the development of new therapeutic tools for use in
the treatment of progressive fibrosing renal diseases. Using our growing
knowledge, treatment strategies need to be identified that prevent progression
more effectively, as well as inducing regression of developed renal fibrosis.
This is likely by combining compounds that interfere with a variety of targets
simultaneously.

Publication Types:
Review

PMID: 15816501 [PubMed - indexed for MEDLINE]

13: Rev Med Suisse. 2005 Feb 23;1(8):568-70, 572-3.

[BMP-7 (Bone morphogenetic protein-7): a future treatment for chronic renal
failure?]

[Article in French]

Niksic L, Martin PY.

Service de nephrologie, Departement de Medecine Interne, Hopitaux Universitaires
de Geneve. Laurent.niksic@hcuge.ch

Renal fibrosis is an evolutive process frequently leading to end stage renal
failure. Several studies have demonstrated the dominant and mutually
antagonistic roles of two proteins from the transforming growth factor
superfamily. BMP-7 has a protective effect on the kidney, by decreasing
apoptosis, maintaining and restoring the epithelial phenotype and dysplaying
anti-fibrotic activity. The mechanisms through which TGF beta 1 favours fibrosis
are still unclear, although most of its activity appears to be due to antagonism
of the effects of BMP-7. Animal studies are very encouraging, as exogenous BMP-7
has allowed stabilisation and even regression of renal fibrosis with a
concomitant stabilisation or improvement of renal function. The therapeutic
implications of these findings are promising.

Publication Types:
Review

PMID: 15794307 [PubMed - indexed for MEDLINE]

14: J Am Soc Nephrol. 2005 Apr;16(4):917-28. Epub 2005 Mar 2.

Low turnover osteodystrophy and vascular calcification are amenable to skeletal
anabolism in an animal model of chronic kidney disease and the metabolic
syndrome.

Davies MR, Lund RJ, Mathew S, Hruska KA.

Department of Medicine, Washington University School of Medicine, Campus Box
8208, 5th Floor MPRB, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.

LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the
metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney
disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an
efficacious agent in treating animal models of renal osteodystrophy. Here,
LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions
in bone formation rates, associated with increased VC and hyperphosphatemia.
Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened
and hyperphosphatemia persisted. BMP-7 treatment corrected the
hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible
with skeletal phosphate deposition leading to reduced plasma phosphate and
removal of a major stimulus to VC. A pathologic link between abnormal bone
mineralization and VC through the serum phosphorus was supported by the partial
effectiveness of directly reducing the serum phosphate by a phosphate binder
that had no skeletal action. Thus, in this model of the metabolic syndrome with
CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone
turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the
skeletal anabolic agent BMP-7, in part through deposition of phosphate and
increased bone formation.

PMID: 15743994 [PubMed - indexed for MEDLINE]

15: J Biol Chem. 2005 Mar 4;280(9):8094-100. Epub 2004 Dec 9.

Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult
renal fibroblasts and facilitates regeneration of injured kidney.

Zeisberg M, Shah AA, Kalluri R.

Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical
Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

In the kidney, a unique plasticity exists between epithelial and mesenchymal
cells. During kidney development, the metanephric mesenchyme contributes to
emerging epithelium of the nephron via mesenchymal to epithelial transition
(MET). In the injured adult kidney, renal epithelia contribute to the generation
of fibroblasts via epithelial-mesenchymal transition, facilitating renal
fibrosis. Recombinant human bone morphogenic protein (BMP)-7, a morphogen that
is essential for the conversion of epithelia from condensing mesenchyme during
kidney development, enhances the repair of tubular structures in the kidney. In
this setting, BMP-7 inhibits epithelial-mesenchymal transition involving adult
renal epithelial tubular cells and decreases secretion of type I collagen by
adult renal fibroblasts. In search of a mechanism behind the ability of BMP-7 to
repair damaged renal tubules, we hypothesized that systemic treatment with BMP-7
might induce MET involving adult renal fibroblasts in the injured kidney,
generating functional epithelial cells. Here we report that BMP-7 induces
formation of epithelial cell aggregates in adult renal fibroblasts associated
with reacquisition of E-cadherin expression and decreased motility, mimicking
the effect of BMP-7 on embryonic metanephric mesenchyme to generate epithelium.
In addition, we provide evidence that BMP-7-mediated repair of renal injury is
associated with MET involving adult renal interstitial fibroblasts in mouse
models for renal fibrosis. Collectively, these findings suggest that adult renal
fibroblasts might retain parts of their original embryonic imprint and
plasticity, which can be re-engaged by systemic administration of BMP-7 to
mediate repair of tubular injury in a fibrotic kidney.

PMID: 15591043 [PubMed - indexed for MEDLINE]

16: J Am Soc Nephrol. 2005 Jan;16(1):79-89. Epub 2004 Dec 1.

Comment in:
J Am Soc Nephrol. 2005 Jan;16(1):9-11.

Bone morphogenic protein-7 inhibits monocyte-stimulated TGF-beta1 generation in
renal proximal tubular epithelial cells.

Zhang XL, Selbi W, de la Motte C, Hascall V, Phillips AO.

Institute of Nephrology, University of Wales College of Medicine, Heath Park,
Cardiff CF14 4XN, United Kingdom.

It has been demonstrated that bone morphogenic protein-7 (BMP-7) stimulates
formation of hyaluronan (HA)-based cables on the cell surface of renal proximal
tubular cells and that these cables mediate monocyte binding. Furthermore,
interaction of monocytes with proximal tubule cell (PTC) surface intracellular
adhesion molecule (ICAM) stimulates the synthesis of TGF-beta1. This study
examined the effect of BMP-7 on monocyte-stimulated TGF-beta1 synthesis under
conditions of basal and stimulated ICAM expression. Monocyte (U937
cells)-dependent stimulation of TGF-beta1 promoter activity and protein
synthesis was reduced by addition of BMP-7 for 24 h before addition of U937
cells. Removal of cell surface HA or inhibition of monocyte interaction with HA
using antibody to CD44 prevented this effect of BMP-7. These data suggest that
BMP-7 enhances HA-dependent binding and reduces ICAM-dependent binding, which is
known to stimulate TGF-beta1 synthesis. This hypothesis was examined further by
stimulation of PTC ICAM expression by TNF-alpha. After TNF-alpha stimulation,
monocyte-dependent TGF-beta1 synthesis increased. This was abrogated by
inhibition of ICAM-CD18 interactions. TNF-alpha stimulation alone did not
increase TGF-beta1 synthesis. TNF-alpha stimulation of PTC in the presence of
BMP-7 failed to increase monocyte-dependent TGF-beta1 stimulation. Although
stimulation of PTC by BMP-7 alone decreased cell surface ICAM expression, it did
not affect TNF-alpha-induced ICAM expression. The effect of BMP-7 on TGF-beta1
synthesis in TNF-alpha-stimulated cells was abrogated by disruption of CD44-HA
interactions, suggesting that it was due to increased monocyte binding to HA on
the cell surface.

PMID: 15574511 [PubMed - indexed for MEDLINE]

17: J Nephrol. 2004 Jul-Aug;17(4):496-503.

Prevention of progressive fibrosis in chronic renal diseases: antifibrotic
agents.

Negri AL.

Physiology and Biophysics Department, University of Salvador, Buenos Aires,
Argentina. negri@casasco.com.ar

Renal fibrogenesis can be induced by several injury mechanisms in different
renal diseases, but ultimately produces identical fibrotic changes in the
kidney. Recently, a number of agents that can inhibit extracellular matrix (ECM)
accumulation have been studied, suggesting a therapeutic utility in the
treatment of fibrotic renal disease. Pirfenidone (PFD) is a small molecule that
has shown efficacy in various models of renal damage with progressive disease.
The apparent absence of toxicity in PFD suggests that it does not affect the
normal ECM turnover. Relaxin, a hormone belonging to the insulin-like growth
factor (IGF) family, has antifibrotic properties and has been used for a long
time to induce transient remissions in patients with scleroderma. Only recently
it has been shown to drastically reduce corticomedular scarring in animal
models. Bone morphogenetic protein 7 (BMP-7), a member of the transforming
growth factor beta (TGF-beta) superfamily, has been shown to reduce glomerular
and interstitial area, and prevent glomerular sclerosis even more effectively
than enalapril. Finally, hepatocyte growth factor (HGF), with its multiple
biological activities on a wide variety of cells, has an organotrophic role in
the regeneration and protection of various organs including the kidney. Both
endogenous and exogenous HGF have shown suppressive effects on renal fibrosis
and chronic renal damage in various animal models. The inhibition of
pathological ECM accumulation and the modulation of fibrotic mechanisms with
these new antifibrotic agents is an achievable goal and could confer further
benefits beyond the current therapies used in the treatment of chronic renal
diseases.

Publication Types:
Review

PMID: 15372410 [PubMed - indexed for MEDLINE]

18: Development. 2004 Sep;131(18):4593-605.

TGFbeta superfamily signals are required for morphogenesis of the kidney
mesenchyme progenitor population.

Oxburgh L, Chu GC, Michael SK, Robertson EJ.

Department of Molecular and Cellular Biology, Harvard University, 16 Divinity
Avenue, Cambridge, MA 02138, USA.

The TGFbeta superfamily plays diverse and essential roles in kidney development.
Gdf11 and Bmp4 are essential for outgrowth and positioning of the ureteric bud,
the inducer of metanephric mesenchyme. During nephrogenesis, Bmp7 is required
for renewal of the mesenchyme progenitor population. Additionally, in vitro
studies demonstrate inhibitory effects of BMPs and TGFbetas on collecting duct
branching and growth. Here, we explore the predicted models of TGFbeta
superfamily function by cell-specific inactivation of Smad4, a key mediator of
TGFbeta signaling. Using a HoxB7cre transgene expressed in ureteric bud and
collecting duct, we find that development of the collecting duct is Smad4
independent. By contrast, removal of Smad4 in nephrogenic mesenchyme using the
Bmp7(cre/+) allele leads to disorganization of the nephrogenic mesenchyme and
impairment of mesenchyme induction. Smad4-deficient metanephric mesenchyme does
not display defects in inducibility in LiCl or spinal cord induction assays.
However, in situ hybridization and lineage analysis of Smad4 null mesenchyme
cells at E11.5 show that the nephrogenic mesenchyme does not aggregate tightly
around the ureteric bud tips, but remains loosely associated, embedded within a
population of cells expressing markers of both nephrogenic mesenchyme and
peripheral stroma. We conclude that the failure of recruitment of nephrogenic
mesenchyme leaves a primitive population of mesenchyme at the periphery of the
kidney. This population is gradually depleted, and by E16.5 the periphery is
composed of cells of stromal phenotype. This study uncovers a novel role for
TGFbeta superfamily signaling in the recruitment and/or organization of the
nephrogenic mesenchyme at early time-points of kidney development. Additionally,
we present conclusive genetic lineage mapping of the collecting duct and
nephrogenic mesenchyme.

PMID: 15342483 [PubMed - indexed for MEDLINE]

19: Nephron Exp Nephrol. 2004;97(4):e123-35.

Exogenous bone morphogenetic protein-7 fails to attenuate renal fibrosis in rats
with overload proteinuria.

Ikeda Y, Jung YO, Kim H, Oda T, Lopez-Guisa J, Maruvada R, Diamond DL, Martin
KJ, Wing D, Cai X, Eddy AA.

Children's Hospital and Regional Medical Center, University of Washington,
Seattle, Wash 98105, USA.

BACKGROUND: Bone morphogenetic protein-7 (BMP-7) plays a critical role in renal
development, accelerates recovery from acute renal injury, and more recently it
has been shown to delay progressive renal disease. The present study was
designed to investigate the effect of BMP-7 on interstitial fibrosis in the rat
protein-overloaded model. METHODS: Renal disease was induced in 26 rats by daily
intraperitoneal injections of bovine serum albumin (BSA); controls (n = 28) were
injected with saline. Half of the rats in each group were treated with human
recombinant BMP-7 (300 microg/kg i.p. 3 times weekly) and half with placebo.
Animals were killed after 3 or 6 weeks. RESULTS: Compared to the saline control
groups, the BSA groups had evidence of chronic renal disease: significantly
increased urinary protein excretion rates; total kidney collagen content, and
increased fibronectin and collagen III interstitial areas. By 6 weeks the BSA +
BMP-7 group compared to the BSA + placebo group had a nonsignificant decrease in
blood urea nitrogen (40 +/- 13 vs. 46 +/- 11 mg/dl), total kidney collagen (10.8
+/- 2.1 vs. 12.2 +/- 3.5 microg/kidney), fibronectin interstitial area (23 +/- 4
vs. 25 +/- 8%) and collagen III interstitial area (22 +/- 6 vs. 28 +/- 7%).
Despite these results, renal gene expression profiles actually predicted worse
fibrosis in the BSA + BMP-7 group with significantly higher total kidney mRNA
levels for alpha(1)(III) procollagen (2.8 +/- 0.5 vs. 1.6 +/- 0.6, p < 0.05) and
fibronectin at 6 weeks (1.9 +/- 0.3 vs. 1.2 +/- 0.5, p < 0.05). Renal BMP-7 mRNA
levels at 6 weeks were significantly increased in the BSA + placebo group
compared to the saline + placebo group with no difference between the BSA +
BMP-7 and the BSA + placebo groups. Both cortical and medullary tubules
expressed BMP-7 protein but BMP-7 was only detected in the tubular lumina and
urine of proteinuric animals. CONCLUSIONS: In rats with protein-overload
proteinuria, renal tubules continue to express BMP-7 but some of the endogenous
protein is secreted into the urinary space. Administration of exogenous
recombinant BMP-7 had no effect on proteinuria but was associated with a
nonsignificant trend towards less interstitial fibrosis at 6 weeks despite
significantly higher kidney extracellular matrix gene mRNA levels. These
findings suggest that BMP-7 treatment may have anti-fibrotic effects through
enhancement of matrix turnover, although overall these effects are modest in
proteinuric states in the absence of significant tubular epithelial cell
apoptosis and epithelial-mesenchymal transition. Copyright 2004 S. Karger AG,
Basel

PMID: 15331933 [PubMed - indexed for MEDLINE]

20: Toxicol Pathol. 2004 Jul-Aug;32(4):384-92.

Osteogenic Protein-1: gene expression and treatment in rat remnant kidney model.

Dube PH, Almanzar MM, Frazier KS, Jones WK, Charette MF, Paredes A.

Department of Nephrology, Miami Children's Hospital, Miami, Florida, USA.

Osteogenic Protein-1 (OP-1) is a bone morphogen involved in tissue repair and
development. We have shown that OP-1 is downregulated during acute ischemic
renal injury. Here we report the use of the rat remnant kidney model (RRKM) to
evaluate changes in kidney OP-1 expression during chronic injury, and determine
if treatment with recombinant human OP-I (rhOP-1) aids in recovery from injury.
Sprague-Dawley rats were subjected to kidney decapsulation (Cx) or 5/6
nephrectomy (Nx). Serum for BUN and creatinine and tissue for histology and mRNA
analysis were collected at: 2, 10. and 12-14 wks post Nx. We show kidney OP-1
mRNA levels were downregulated at 2 and 12-14 wks post Nx. To determine the
effect of rhOP-1 in the RRKM, rhOP-1 (0.25, 2.5 or 25 microg/kg) or vehicle (V)
was injected in a second set of rats, 2 weeks after 2/3 left Nx for a total of
six doses. Nx rats treated with rhOP-1 showed significantly increased tubular
regeneration (increased mitotic figures, polyoid infolding, and tubular
epithelialhyperplasia) in a dose dependent manner without changes in glomerular
or tubular damage. rhOP-1 stimulates tubular epithelial cell regeneration,early
in the repair process in a chronic renal failure model, before significant
fibrosis is established.

PMID: 15307210 [PubMed - indexed for MEDLINE]

21: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004 Jun;26(3):274-8.

[Effect of BMP-7 on the transdifferentiation of cultured human tubular
epithelial cell induced by TGF-beta1]

[Article in Chinese]

Tan XY, Zheng FL, Yang JH, Duan L, Li Y, Zhou QG.

Department of Nephrology, PUMC Hospital, CAMS and PUMC, Beijing 100730, China.

OBJECTIVE: To observe the effect of bone morphogenetic protein-7 (BMP-7) on the
transdifferentiation of cultured human tubular epithelial cell (HKC) induced by
TGF-beta1 and to elucidate its possible mechanism. METHODS: The cultured HKC
cells were divided into 5 groups: serum-free group (negative control); single
TGF-beta1 treated group (positive control); single BMP-7 treated group; combined
TGF-beta1 and BMP-7 treated group; and BMP-7 pre-treated group. Expression of
keratin of HKC cells was assessed by indirect enzyme immunohistochemistry (IEI),
expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin by
immunohistological method, percentage of alpha-SMA positive HKC cells by flow
cytometry, and mRNA expression of alpha-SMA, TGF-beta1, and TGF-beta type II
receptor by reverse transcription PCR. RESULTS: The expression of alpha-SMA and
the percentage of alpha-SMA positive HKC cells markedly increased after having
been treated by TGF-beta1 while the expression of E-cadherin and keratin
decreased. In the group pre-treated with BMP-7 (50 ng/ml) and then added with
TGF-beta1 (8 ng/ml), expression of alpha-SMA was significantly lower than in the
positive control group, while expression of E-cadherin and keratin significantly
higher than in the positive control group. Measurement of the percentage of
alpha-SMA positive HKC found significant deference between the combined
TGF-beta1 and BMP-7 treated group and the positive control group (9.7% vs 19.8%;
5.8% vs 19.8%; P < 0.05). Significant difference existed between the BMP-7 (50
ng/ml) pre-treated group and the positive control group (8.7% vs 19.8%, P <
0.05). mRNA expression of alpha-SMA was measured by RT-PCR and the results
showed that it significantly decreased in the group treated or pre-treated with
BMP-7 (50 ng/ml) (15% and 12% of the results in the positive control group,
respectively). The mRNA expression levels of both TGF-beta1 and its type II
receptor significantly decreased (28% and 19%; 47% and 36%, compared with the
positive control group, respectively). CONCLUSION: Transdifferentiation of
cultured renal epithelial cell induced by TGF-beta1 can be inhibittd by certain
levels of BMP-7, cultured together with TGF-beta1 or pretreated. BMP-7 can
prevent and inhibit the mRNA expression of TGF-beta1 and its type II receptor,
which may be an important mechanism by which BMP-7 inhibit the
transdifferentiation of renal tubular epithelial cell.

PMID: 15266829 [PubMed - indexed for MEDLINE]

22: Curr Opin Nephrol Hypertens. 2004 Jul;13(4):417-22.

Bone morphogenetic protein 7: a novel treatment for chronic renal and bone
disease.

Li T, Surendran K, Zawaideh MA, Mathew S, Hruska KA.

Department of Medicine, Washington University School of Medicine, St Louis,
Missouri, USA.

PURPOSE OF REVIEW: When last reviewed, bone morphogenetic protein 7 was
presented as a potential new renal therapeutic agent, with multiple efficacies
in chronic kidney disease. The object of this review is to describe progress
from many sources since then in support or denial of the hypothesis. RECENT
FINDINGS: Bone morphogenetic protein 7 has been shown to be an effective defence
in several forms of chronic kidney disease in animal models, and its mechanisms
of action have begun to be elucidated. Bone morphogenetic protein 7 inhibits
tubular epithelial cell de-differentiation, mesenchymal transformation and
apoptosis stimulated by various renal injuries. Bone morphogenetic protein 7
preserves glomerular integrity and inhibits injury-mediated mesangial matrix
accumulation. In renal osteodystrophy, bone morphogenetic protein 7 affects
osteoblast morphology and number, eliminates peritrabecular fibrosis, decreases
bone resorption, and increases bone formation in secondary hyperparathyroidism.
Bone morphogenetic protein 7 restores normal rates of bone formation in the
adynamic bone disorder. Bone morphogenetic protein 7 is broadly efficacious in
renal osteodystrophy, and importantly increases the skeletal deposition of
ingested phosphorus and calcium, improving ion homeostasis in chronic kidney
disease. Bone morphogenetic protein 7 was shown to prevent vascular
calcification in a model of chronic kidney disease associated with the
restoration of osteocalcin expression to normal tissue-restricted sites.
SUMMARY: Bone morphogenetic protein 7 may be a powerful new therapeutic agent
for chronic kidney disease, with the novel attribute of not only treating the
kidney disease itself, but also directly inhibiting some of the most important
complications of the disease state.

Publication Types:
Review

PMID: 15199292 [PubMed - indexed for MEDLINE]

23: Nephron Exp Nephrol. 2004;97(1):e26-32.

Bone morphogenetic protein-7 from serum of pregnant mice is available to the
fetus through placental transfer during early stages of development.

Borovecki F, Jelic M, Grgurevic L, Sampath KT, Bosukonda D, Vukicevic S.

Department of Anatomy, Medical School University of Zagreb, Zagreb, Croatia.

BACKGROUND: BMP-7 is an important mediator of metanephric mesenchyme
differentiation during kidney development. Gene knockout studies have shown that
BMP-7 null mutation mice die shortly after birth due to renal failure, although
the induction of metanephric structures has initially occurred (E11-E13).
MATERIALS AND METHODS: Iodinated BMP-7 was injected into the tail vein of
pregnant mice and its availability to tissues and fetuses was further analyzed
by tissue uptake, LM autoradiography and SDS-PAGE electrophoresis. RESULTS:
Studies on the distribution of 125I-BMP-7 injected through the tail vein of
pregnant mice indicated that 125I-BMP-7 passed across the placenta and localized
in developing fetal organs, in particular kidneys, up to day 14 of gestation. At
later stages of pregnancy 125I-BMP-7 did not pass the trophoblasts of the
placental barrier and did not enter the fetal blood vessels. CONCLUSION: The
analysis of the distribution of 125I-BMP-7 from pregnant mice to fetal organs,
in particular the kidney, suggests a cross-over of maternal circulating BMP-7 to
the fetus through the placental barrier. Copyright 2004 S. Karger AG, Basel

PMID: 15153758 [PubMed - indexed for MEDLINE]

24: J Am Soc Nephrol. 2004 May;15(5):1199-211.

BMP-7 modulates hyaluronan-mediated proximal tubular cell-monocyte interaction.

Selbi W, de la Motte C, Hascall V, Phillips A.

Institute of Nephrology, University of Wales College of Medicine, Heath Park,
Cardiff, Wales, United Kingdom.

Increased synthesis of hyaluronan (HA) in the renal corticointerstitium has been
documented in renal injury, although the functional significance of this is
unclear. The aim of the work presented in the current study was to examine the
role of HA in monocyte binding by proximal tubular cells (PTC). Using the PTC
line HK-2, the authors show that unstimulated cells formed pericellular HA
cable-like structures that bound mononuclear leukocytes via their cell surface
CD44. Stimulation with bone morphogenic protein-7 (BMP-7) led to increased
formation of HA cable-like structures and also a dose-dependent increase in
CD44-dependent binding of radiolabeled U937 cells. The authors have previously
demonstrated that stimulation with IL-1beta is a potent stimulus for induction
of HAS gene expression and HA synthesis. In this study, addition of IL-1beta
influenced neither HA cable formation nor CD44-mediated monocyte binding. Rather
IL-1beta led to an increase in intercellular adhesion molecule (ICAM)-dependent
monocyte binding. Characterization of HA synthesis by addition of
[(3)H]-glucosamine to cells at the time of stimulation demonstrated that
increased HA in response to IL-1 was most apparent in the culture medium, while
BMP-7 led to an increase in cell associated HA. Stimulation of cells with BMP-7
induced HAS2 mRNA expression and decreased the expression of Hyal1 and Hyal2. In
contrast to BMP-7, IL-1beta did not influence Hyal expression. The data
presented in this manuscript provide insight into how alterations in HA
synthesis in the renal cortex may be involved in modulation of the interaction
between infiltrating inflammatory cells and resident cells.

PMID: 15100360 [PubMed - indexed for MEDLINE]

25: J Biol Chem. 2004 May 28;279(22):23200-6. Epub 2004 Mar 26.

Bone morphogenetic protein-7 signals opposing transforming growth factor beta in
mesangial cells.

Wang S, Hirschberg R.

Harbor-UCLA Research and Education Institute, UCLA, Torrance, California 90502,
USA.

Bone morphogenetic protein-7 (BMP7) is expressed in adult kidney and reduces
renal fibrogenesis when given exogenously to rodents with experimental chronic
nephropathies. In mesangial cells that regulate glomerular fibrosis in vivo,
BMP7 inhibits transforming growth factor beta (TGF-beta)-driven fibrogenesis,
primarily by preventing the TGF-beta-dependent down-regulation of matrix
degradation and up-regulation of PAI-1. The signals and mechanisms of the BMP7
opposition to actions of TGF-beta are unknown. Here we show in mesangial cells
that BMP7 reduces nuclear accumulation of Smad3 and blocks the transcriptional
up-regulation of the TGF-beta/Smad3 target, CAGA-lux. Smad5 knock-down impairs
the ability of BMP7 to interfere with the activation of CAGA-lux and the
accumulation of PAI-1 by TGF-beta indicating that Smad5 is required. Smad5
knock-down also reduces the rise in Smad6 upon BMP7. Forced expression of smad5
(found to be the preferred BMP7-induced receptor-activated Smad signal in
mesangial cells) or of smad6 mimics BMP7 in opposing the increase in
transcriptional activation of PAI-1 and its secretion upon TGF-beta. This
suggests a model for the BMP7-induced opposition to TGF-beta-dependent mesangial
fibrogenesis requiring Smad5; the model involves the inhibitory Smad6 downstream
of Smad5 as well as reduced availability of Smad3 in the nucleus. BMP7 does not
require signaling through Erk1/2, p38, or JNK and does not utilize the TGF-beta
transcriptional co-repressors Ski or SnoN in mesangial cells. These studies
provide first insights into mechanisms through which BMP7 opposes
TGF-beta-induced glomerular fibrogenesis.

PMID: 15047707 [PubMed - indexed for MEDLINE]

26: Nephrol Dial Transplant. 2004 Apr;19(4):759-61.

Are there endogenous molecules that protect kidneys from injury? The case for
bone morphogenic protein-7 (BMP-7).

Zeisberg M, Muller GA, Kalluri R.

Publication Types:
Editorial
Review

PMID: 15031324 [PubMed - indexed for MEDLINE]

27: Biochem Biophys Res Commun. 2004 Apr 2;316(2):490-500.

USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the
kidney.

Yanagita M, Oka M, Watabe T, Iguchi H, Niida A, Takahashi S, Akiyama T, Miyazono
K, Yanagisawa M, Sakurai T.

Yanagisawa Orphan Receptor Project, Exploratory Research for Advanced Technology
(ERATO), Japan Science and Technology Agency, Tokyo 135-0064, Japan.
motoy@orphan.miraikan.jst.go.jp

Bone morphogenetic proteins (BMPs) play critical roles in cellular
proliferation, differentiation, and programmed cell death in multiple tissues.
An increasing body of recent evidence has suggested that classes of molecules
collectively termed BMP antagonists play important roles for the local
regulation of BMP actions by binding BMPs and neutralizing their activities.
Uterine sensitization-associated gene-1 (USAG-1) was previously reported as a
gene of unknown function, preferentially expressed in sensitized endometrium of
the rat uterus. Here, we show that USAG-1 is abundantly expressed in the kidney
and functions as a BMP antagonist. Recombinant USAG-1 binds directly to BMPs and
antagonizes the BMP-mediated induction of alkaline phosphatase in C2C12 cells.
USAG-1 also induces formation of secondary axis and/or hyperdorsalization when
its mRNA is injected to Xenopus embryos. In the early stage of mouse
embryogenesis, USAG-1 is expressed in the first and second branchial arches and
in metanephros, while in later stages the expression is confined to renal
tubules and ameloblasts of teeth. Postnatally, the expression is further
restricted to distal tubules of kidney, in a pattern similar to the localization
of BMP-7, which has been shown to be important in the development of kidney and
preservation of adult renal functions under pathological stresses. Collectively,
we suggest that USAG-1 is a BMP antagonist that interacts with BMP-7 in the
developing and adult kidney.

PMID: 15020244 [PubMed - indexed for MEDLINE]

28: Transplant Proc. 2004 Jan-Feb;36(1):131-3.

Cyclosporine-A induced nephrotoxicity is associated with decreased renal bone
morphogenetic protein-7 expression in rats.

Tuglular S, Gogas Yavuz D, Cakalagaoglu F, Citak L, Arikan H, Kocak H, Ozener C,
Akoglu E.

Section of Nephrology, Marmara University Medical School, Istanbul, Turkey.
serhantuglular@yahoo.com

The aim of our study was to investigate bone morphogenetic protein-7 (BMP-7)
expression in a rat model of chronic cyclosporine (CsA) toxicity compare with
healthy controls, as well as the influence of treatment with the
angiotensin-converting enzyme inhibitor (ACEI) quinapril. Twenty-four male
Wistar rats were divided into groups of eight animals treated with CsA (15 mg/kg
intraperitoneally) for 8 weeks (CsA group) without or with quinapril (10 mg/kg
per day in the drinking water: CsA group + Q) for comparison with healthy
controls (H group). The renal tissues were examined by light microscopy for CsA
toxicity; specifically, tubulointerstitial damage and afferent arteriolopathy as
well as BMP-7 expression were semiquantitatively scored by immunohistochemical
staining. Mean CsA levels were 1982 ng/mL and 1968 ng/mL for the CsA and CsA + Q
groups, respectively. At the end of the study period, the mean serum creatinine
levels were 0.8 +/- 0.2 mg/dL, 1.6 +/- 0.8 mg/dL, and 1.4 +/- 0.8 mg/dL for the
H, CsA, and CsA + Q groups, respectively. Interstitial fibrosis, tubular
atrophy, and afferent arteriolar hyalinization were present in the CsA group
and, to a lesser degree, in the CsA + Q group, compared with the H group.
CsA-treated rats displayed significantly decreased BMP-7 expression compared
with healthy controls (P <.0005). BMP-7 expression was higher among the CsA + Q
group than the the group CsA group. In a rat model histologic changes
characteristic of CsA-induced nephrotoxicity are associated with decreased
expression of BMP-7, which seems to be at least partially restored by ACE
inhibition.

PMID: 15013323 [PubMed - indexed for MEDLINE]

29: J Mol Med. 2004 Mar;82(3):175-81. Epub 2004 Jan 30.

The role of epithelial-to-mesenchymal transition in renal fibrosis.

Zeisberg M, Kalluri R.

Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical
Center and Harvard Medical School, Boston, MA 02115, USA.

Epithelial-to-mesenchymal transition (EMT) involving injured epithelial cells
plays an important role in the progression of fibrosis in the kidney. Tubular
epithelial cells can acquire a mesenchymal phenotype, and enhanced migratory
capacity enabling them to transit from the renal tubular microenvironment into
the interstitial space and escape potential apoptotic cell death. EMT is a major
contributor to the pathogenesis of renal fibrosis, as it leads to a substantial
increase in the number of myofibroblasts, leading to tubular atrophy. However,
recent findings suggest that EMT involving tubular epithelial cell is a
reversible process, potentially determined by the surviving cells to facilitate
the repopulation of injured tubules with new functional epithelia. Major
regulators of renal epithelial cell plasticity in the kidney are two
multifunctional growth factors, bone morphogenic protein-7 (BMP-7) and
transforming growth factor beta1 (TGF-beta1). While TGF-beta1 is a
well-established inducer of EMT involving renal tubular epithelial cells, BMP-7
reverses EMT by directly counteracting TGF-beta-induced Smad-dependent cell
signaling in renal tubular epithelial cells. Such antagonism results in the
repair of injured kidneys, suggesting that modulation of epithelial cell
plasticity has therapeutic advantages.

Publication Types:
Review

PMID: 14752606 [PubMed - indexed for MEDLINE]

30: J Am Soc Nephrol. 2004 Feb;15(2):359-69.

Successful treatment of an adynamic bone disorder with bone morphogenetic
protein-7 in a renal ablation model.

Lund RJ, Davies MR, Brown AJ, Hruska KA.

Renal Division, Department of Medicine, Washington University School of
Medicine, St. Louis, Missouri 63110, USA.

An adynamic bone disorder (ABD) is an important complication of chronic kidney
disease (CKD) of unknown etiology for which there is no adequate treatment.
Reported is an animal model of ablative CKD complicated by an ABD characterized
by the absence of secondary hyperparathyroidism and its successful treatment
with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult
mice were subjected to electrocautery of the right kidney followed by left
nephrectomy. Animals were randomized into groups fed normal chow or fed
low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in
CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia,
secondary hyperparathyroidism, and a mild osteodystrophy developed in the
CKD/chow-fed group, as expected. When dietary phosphorus was restricted and
calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca,
PO(4), and parathyroid hormone levels were maintained normal. A significant ABD
developed in the ABD group characterized by significant depressions in
osteoblast number, perimeters, bone formation rates, and mineral apposition
rates when compared with the sham-operated, chow-fed group. The abnormal
skeletal histomorphometry was reversed by BMP-7 therapy to normal values and
significantly improved from the ABD group (P < 0.05). The sham-operated
low-phosphate/calcitriol-fed control group and the CKD
low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with
the other groups (P < 0.05). ABD produced in mice with CKD in the absence of
hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7,
associated with a reduction in plasma phosphorus.

PMID: 14747382 [PubMed - indexed for MEDLINE]

31: Cells Tissues Organs. 2004;176(1-3):109-19.

Different effects of BMP-2 on marrow stromal cells from human and rat bone.

Osyczka AM, Diefenderfer DL, Bhargave G, Leboy PS.

Department of Biochemistry, School of Dental Medicine, University of
Pennsylvania, Philadelphia, Pa., USA.

Bone morphogenetic proteins (BMPs) promote the differentiation of
osteoprogenitor cells, and also induce osteogenesis in bone marrow stromal cells
(MSC) from rats and mice. However, compared to results with animal models, BMPs
are relatively inefficient in inducing human MSC to undergo osteogenesis, and
are much less effective in promoting bone formation in human clinical trials.
Previous studies indicated that, while human MSC respond to dexamethasone with
elevated levels of the osteoblast marker alkaline phosphatase, most isolates of
human MSC fail to show alkaline phosphatase induction in response to BMP-2,
BMP-4, or BMP-7. Several other genes known to be induced by BMPs are
appropriately regulated; thus, human MSC are capable of some BMP-activated
signaling. Analysis of the BMP receptors ALK-3 and ALK-6 indicated that,
although ALK-6 mRNA was not expressed in human MSC, overexpressing a
constitutively active ALK-6 receptor did not induce elevated alkaline
phosphatase. Real-time RT-PCR was used to investigate expression of several
osteoblast-related transcription factors in MSC after 6 days' exposure to BMP2
or dexamethasone. Msx-2, a transcription factor that has been reported to
inhibit differentiation of osteoprogenitor cells, showed 10-fold elevation in
BMP-2-treated human MSC, but not in BMP-2-treated rat MSC. Overexpression of
Msx-2 in human and rat MSC, however, did not alter alkaline phosphatase levels,
which suggests that absence of BMP-stimulated alkaline phosphatase was not
caused by the BMP-2-induced increase in Msx-2. Although Runx2 isoforms have been
implicated in control of osteoblast differentiation, levels of this
transcription factor were unaffected by BMP treatment. Expression of the FKHR
transcription factor, which has been reported to regulate alkaline phosphatase
transcription in mouse cells, showed a modest increase in response to BMP-2, but
a much greater increase in dexamethasone-treated cells. We propose that BMP
regulation of the bone/liver/kidney alkaline phosphatase gene is indirect,
requiring expression of new transcription factor(s) that behave differently in
rodent and human MSC. Copyright 2004 S. Karger AG, Basel

PMID: 14745240 [PubMed - indexed for MEDLINE]

32: Semin Nephrol. 2004 Jan;24(1):25-38.

Kidney-bone, bone-kidney, and cell-cell communications in renal osteodystrophy.

Hruska KA, Saab G, Chaudhary LR, Quinn CO, Lund RJ, Surendran K.

Department of Pediatrics, Washington University School of Medicine, St Louis, MO
63110, USA. hruska_k@wustl.edu

The relationship between bone and the kidney in renal osteodystrophy is a
complex interplay of kidney to bone connections, bone to kidney connections, and
cell to cell connections. In addition, such interactions have a profound effect
on the vasculature. In this review, we discuss the role of the bone
morphogenetic proteins (BMPs) in the skeleton, kidney, and vasculature. In
addition, we propose that deficiencies of these BMPs seen in chronic kidney
disease (CKD) result in decreased bone remodeling and a compensatory secondary
hyperparathyroidism (high turnover state). Treatment of the hyperparathyroidism
blocks this compensatory arm and thus decreased bone remodeling occurs (low
turnover). We review animal models of CKD in which treatment with BMP-7 resulted
in normalization of both high and low turnover states. Finally, we discuss
vascular calcification as it relates to bone metabolism. We discuss the roles of
BMP-7 and 2 other bone regulatory proteins, osteoprotegerin (OPG) and alpha2-HS
glycoprotein (AHSG, human fetuin), in the human vasculature and their
implications for vascular calcification.

Publication Types:
Review

PMID: 14730507 [PubMed - indexed for MEDLINE]

33: J Biol Chem. 2004 Mar 26;279(13):12051-9. Epub 2004 Jan 12.

p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell
morphogenesis and is regulated by Smad1.

Hu MC, Wasserman D, Hartwig S, Rosenblum ND.

Division of Nephrology, Program in Developmental Biology, The Hospital for Sick
Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G
1X8, Canada.

Bone morphogenetic protein (BMP)-7 exerts dose-dependent stimulatory and
inhibitory effects during renal branching morphogenesis. Previously, we
identified an inhibitory role for activin-like kinase receptors and Smad1 in
BMP-dependent inhibition (Piscione, T. D., Phan, T., and Rosenblum, N. D. (2001)
Am. J. Physiol. 280, F19-F33). Here we demonstrate a novel role for p38
mitogen-activated kinase (p38(MAPK)) in BMP7-dependent stimulatory signaling.
Stimulatory doses (0.25 nm) of BMP7 increased p38(MAPK) activity and stimulated
phosphorylation of endogenous activating transcription factor 2 (ATF2) in a
p38(MAPK)-dependent manner in murine inner medullary collecting duct (mIMCD-3)
cells. In contrast, high doses (10 nm) of BMP7 inhibited p38(MAPK) activity and
phosphorylation of endogenous ATF2. Treatment with BMP7 exerted no significant
effect on the levels of the phosphorylated forms of endogenous SAPK/JNK or p44
and p42 (ERK1 and ERK2) protein kinases. To investigate the functional
importance of p38(MAPK) signaling, we showed that SB203580, a p38(MAPK)
inhibitor, blocked the stimulatory effect of BMP7 on mIMCD-3 cell morphogenesis
but had no effect on BMP7-dependent inhibition in a three-dimensional culture
model. To identify mechanisms by which BMP7-dependent inhibitory signaling
suppresses p38(MAPK) activity, we measured p38(MAPK) activity in ligand
independent mIMCD-3 models of enhanced and suppressed Smad signaling. Basal
activity of p38(MAPK) was decreased in mIMCD-3 cells and in embryonic kidney
tissue expressing a constitutively active activin-like kinase receptor, but was
increased in mIMCD-3 cells stably expressing a dominant negative form of Smad1.
We conclude that BMP7 stimulates renal epithelial cell morphogenesis via
p38(MAPK) and that p38(MAPK) activity is negatively regulated by Smad1.

PMID: 14718543 [PubMed - indexed for MEDLINE]

34: Kidney Int Suppl. 2003 Nov;(87):S105-12.

Obstructive nephropathy and renal fibrosis: The role of bone morphogenic
protein-7 and hepatocyte growth factor.

Klahr S, Morrissey J.

Washington University School of Medicine, St. Louis, Missouri, USA.

BACKGROUND: The nephropathy induced by ureteral obstruction is associated with
increased interstitial volume due to matrix deposition, fibroblast
differentiation/proliferation, and monocyte infiltration. Recent studies
indicate that transforming growth factor-beta (TGF-beta) is linked to renal
fibrosis. Tumor necrosis factor (TNF-alpha) has a role in the recruitment of
inflammatory cells. We found that infiltration of macrophages of the
interstitium in unilateral ureteral obstruction (UUO) occurred as early as four
hours after the onset of UUO. METHODS: Recent studies indicate that a renal
tubular development morphogen, bone morphogenetic protein-7 (BMP-7), is
effective in preventing the tubulointerstitial nephritis in the setting of
obstructive nephropathy. The mechanism of action appears to be preservation of
epithelial cell phenotype, inhibition of epithelial-mesenchymal
transdifferentiation, and inhibition of injury-induced epithelial