transforming-growth-factor-beta and Chronic-Kidney-Disease-Mineral-and-Bone-Disorder

The idiom renal osteodystrophy (ROD) represents a heterogeneous pattern of bone disturbances caused by chronic renal insufficiency and concomitant diseases. For the clinical decision of therapy it is most important to differentiate between high and low or adynamic turnover ROD because the therapeutically consequences of these two ends of the ROD spectrum are fundamentally different. Bone histology remains the gold standard for the exact classification of ROD. Serological markers of bone metabolism are not suited for the accurate nomenclature of ROD but are useful for the sequential follow up of ROD after a clear diagnosis has been made. Similarly, radiological diagnosis of ROD using dual energy X-ray absorptiometry (DEXA) or quantitative computer tomography scan (q-CT) is inaccurate and thus more suited for the routine follow up of established disease. Besides mineralization, bone strength and the rate of fractures are strongly determined by the architecture of the bone matrix. This information, however, is also only available on bone biopsy sections and cannot be estimated by non-invasive diagnostic methods. In summary, bone biopsy should be used more liberally for correct classification of bone disease. The sequential follow up and guidance of therapy success can be performed by non-invasive procedures such as biochemical bone marker determination in blood. X-ray imaging and densitometry is suitable only for sequential evaluation of osteoporosis.

Topics: Acid Phosphatase; Alkaline Phosphatase; Biomarkers; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen Type I; Humans; Isoenzymes; Osteocalcin; Osteogenesis; Osteoprotegerin; Parathyroid Hormone; Radiography; Risk Factors; Tartrate-Resistant Acid Phosphatase; Transforming Growth Factor beta

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.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcification, Physiologic; Chronic Kidney Disease-Mineral and Bone Disorder; Fibrosis; Homeostasis; Inflammation; Kidney; Kidney Diseases; Organogenesis; Transforming Growth Factor beta

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.. 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.. 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.

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Chronic Kidney Disease-Mineral and Bone Disorder; Diabetic Nephropathies; Fibrosis; Humans; Kidney Diseases; Kidney Failure, Chronic; Lupus Nephritis; Nephritis, Hereditary; Transforming Growth Factor beta; Vascular Diseases

The pathogenesis of adynamic bone disease (ABD) attributes to calcium overload, active vitamin D (VD) metabolism, increase in inactive PTH (parathyroid hormone) fragments, or derangement of bone metabolism regulation factors. In particular, increased Ca overload plays a critical role in the development of ABD. Thus, alleviated Ca load by sevelamer hydrochloride and appropriate VD administration could be effective on not only prevention, and also treatment of ABD.

Topics: Animals; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcium; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Epoxy Compounds; Glycoproteins; Humans; Hyperparathyroidism, Secondary; Membrane Glycoproteins; Naphthalenes; Osteoprotegerin; Parathyroid Hormone; Polyamines; Polyethylenes; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Calcitriol; Receptors, Calcium-Sensing; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk; Sevelamer; Transforming Growth Factor beta; Vitamin D

Renal osteodystrophy affects all patients with end-stage renal failure, resulting in significant skeletal and extra-skeletal morbidity. The patterns of disease seen in bone are the result of changes in calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism, as well as the effects of uremia. Standard histological techniques, however, give little insight into the altered biological activity or mechanisms of disease at the cellular level. In order to examine the cellular abnormalities in renal bone disease we have performed a series of in situ hybridization studies to examine renal bone cell expression of genes for PTH receptor (PTHR1), transforming growth factor beta (TGF-beta) and insulin growth factor 1 (IGF-I). PTHR1 mRNA was expressed predominantly by osteoblasts, but also by resorbing osteoclasts, suggesting that these cells may be stimulated directly by PTH. Semi-quantitative analysis of gene expression showed down-regulation of PTHR1 mRNA by osteoblasts in renal bone compared with normal, fracture and Pagetic bone. This may be important in the pathogenesis of skeletal resistance seen in end-stage renal failure, altering the "threshold" at which PTH has its effects on bone cells. TGF-beta and IGF-I mRNA expression was also decreased, suggesting that synthesis of these factors, postulated to be mediators of PTH, is also downregulated.

Topics: Animals; Bone Remodeling; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Insulin-Like Growth Factor I; Parathyroid Hormone; Receptors, Parathyroid Hormone; RNA, Messenger; Transforming Growth Factor beta

In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-β and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

Topics: Acute Kidney Injury; Animals; Aorta; Biomarkers; Bone Morphogenetic Proteins; Cell Adhesion Molecules; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Genetic Markers; Glucuronidase; Inhibin-beta Subunits; Kidney; Klotho Proteins; Male; Rats, Wistar; Signal Transduction; Time Factors; Transforming Growth Factor beta; Ureteral Obstruction

High aldosterone level may contribute to pathogenesis of hypertension, vessels damage and cardiovascular system deterioration in chronic kidney disease patients. Besides its classical action via mineralocorticoid receptor, aldosterone is also involved in cell growth, inflammation, oxidative stress, endothelial dysfunction and exerts fibroproliferative effects. The aim of the study was to assess whether aldosterone antagonist treatment may influence serum level of inflammatory, fibrosis, thrombosis and mineral-bone metabolism markers in peritoneal dialysis (PD) patients and blood pressure, aortic stiffness, echocardiographic indices after 12 months of treatment.. Twenty-two patients on PD were assigned to spironolactone treatment in dose of 50 mg daily during 12 months. Fifteen PD patients were assigned to control group. Echocardiographic indices, PVW, SBP, DBP (mean values from ABPM) and biochemical parameters such as: aldosterone, osteopontin, IL-6, selectin-P, TGF-β, PTH, MMP-2 were performed at the beginning and after 12 months in spironolactone and control group.. There were no statistically significant differences in echocardiographic indices, PWV, BP (ABPM readings) and biochemical markers: MMP-2, serum aldosterone, TGF-β, IL-6, selectin-P, PTH level after 12 months of spironolactone treatment. There was statistically significant rise in osteopontin level after 12 months of spironolactone treatment. Episodes of life-threatening hyperkalemia were not reported.. Aldosterone antagonists use in PD patients seems to be safe. Longer duration or higher dosage of spironolactone seems to be more effective in improving cardiovascular system status in PD patients. Further studies are required to determine relationship between mineralocorticoid receptor blockade and mineral-bone disturbances in PD patients.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Biomarkers; Blood Pressure; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Echocardiography; Female; Fibrosis; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 2; Middle Aged; Mineralocorticoid Receptor Antagonists; Osteopontin; P-Selectin; Parathyroid Hormone; Peritoneal Dialysis; Pulse Wave Analysis; Renal Insufficiency, Chronic; Spironolactone; Thrombosis; Transforming Growth Factor beta; Vascular Stiffness

Fetuin-A of hepatic origin circulates in large amounts in serum, but also is expressed in bone, where it is an inhibitor of transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) proteins. Together with matrix GLA protein (MGP), fetuin-A is able to make up a complex with calcium and phosphate that is more soluble than calcium and phosphate alone, preventing its deposition in extraskeletal tissues. Experimental results suggested that this complex is made at bone tissue level. The aim of this study is to evaluate whether serum fetuin-A and MGP are influenced by type of renal osteodystrophy, they correlate with bone histomorphometric and histodynamic parameters, and/or serum levels may influence bone turnover.. Thirty-eight hemodialysis patients who volunteered to undergo a bone biopsy were studied. Patients (27 men, 11 women) had a mean age of 55.2 +/- 11.8 years and dialysis vintage of 75.7 +/- 57.4 months. They were not administered vitamin D or drugs connected with mineral metabolism. They underwent transiliac bone biopsy after tetracycline labeling. Biopsies were performed for histological, histomorphometric, and histodynamic evaluation and aluminum histochemistry. Serum fetuin-A and MGP were measured by using enzyme-linked immunosorbent assay kits.. Serum fetuin-A levels were significantly less than normal, whereas MGP levels were less than the normal average. Fetuin-A levels in patients with hyperparathyroidism, mixed osteodystrophy, and low-turnover osteodystrophy were 0.219 +/- 0.1, 0.27 +/- 0.1, and 0.197 +/- 0.1 ng/mL, respectively (P = not significant). Fetuin-A level significantly correlated inversely with values for several histomorphometric parameters, such as osteoid volume (OV/BV), osteoblastic surface (Ob.S/BS), osteoid surface (OS/BS), and osteoclastic surface (Oc.S/BS). Logistic regression showed odds ratios of 5.3 and 4.9 for the association of high fetuin-A levels with low values for OS/BS and Ob.S/BS, respectively. Results of multiple regression analysis with intact parathyroid hormone and fetuin-A levels as independent variables and OV/BV and Ob.S/BS as dependent variables showed that independent variables correlated significantly with dependent variables, positively for intact parathyroid hormone levels and inversely for fetuin-A levels. MGP levels in patients with hyperparathyroidism, mixed osteodystrophy, and low-turnover osteodystrophy were not significantly different (3.94 +/- 0.86, 3.40 +/- 0.99, and 5.64 +/- 2.4 nmol/L, respectively). By dividing MGP serum values into tertiles, mean values for OV/BV were different (analysis of variance, P < 0.04), with a greater value in the higher MGP tertile. By exclusion of 3 extravariant cases (>3 SDs greater than the mean), 1 case for each type of osteodystrophy, a significant correlation between bone formation rate and MGP serum level was found (P < 0.05). In addition, a significant correlation was found between MGP level and trabecular thickness.. Fetuin-A and MGP levels correlated with bone formation parameters. This association could be caused by an effect of these proteins on bone formation, presumably mediated by the TGF-beta/BMP system. Fetuin-A, as opposed to MGP, is known to inhibit the TGF-beta/BMP complex, a protein-cytokine system that appears to be an important regulator of bone formation and probably a factor with an important role in renal osteodystrophy.

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Blood Proteins; Bone and Bones; Bone Development; Bone Morphogenetic Proteins; Bone Resorption; Calcium-Binding Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Humans; Male; Matrix Gla Protein; Middle Aged; Renal Dialysis; Transforming Growth Factor beta

In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO(4), parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low-density lipoprotein receptor null (LDLR-/-) mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). The finding that high-fat fed LDLR-/- animals with CKD had hyperphosphatemia which was prevented in BMP-7-treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high-fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP-7 treatment corrected the ABD and hyperphosphatemia, owing to BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. 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. Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by 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 affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated wi

Topics: Animals; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Cartilage; Cell Differentiation; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Kidney; Kidney Failure, Chronic; Mice; Osteoblasts; Osteogenesis; Phosphates; Transforming Growth Factor beta; Vascular Diseases

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.

Topics: Animals; Aorta; Aortic Diseases; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Calcinosis; Calcium; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Dietary Fats; Dose-Response Relationship, Drug; Female; Kidney Diseases; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Parathyroid Glands; Phosphates; Receptors, LDL; Transforming Growth Factor beta

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.

Topics: Animals; Aorta, Thoracic; Bone Diseases; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Calcium; Calcium Carbonate; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Dietary Fats; Disease Progression; Female; Hyperparathyroidism; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Osteoblasts; Osteogenesis; Phosphates; Renal Insufficiency, Chronic; Transforming Growth Factor beta

There is growing evidence pointing to an involvement of cytokines and growth factors in renal osteodystrophy. In this study, the expression of interleukin-l beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and basic fibroblast growth factor (bFGF) in bone biopsies taken from uremic patients before and 1 year after parathyroidectomy (PTX) was evaluated. Biochemical features and histomorphometric outcome were also studied.. Iliac bone biopsies were taken before and 1 year after PTX in nine uremic patients with severe hyperparathyroidism (HPT). Immunohistochemical techniques were used to identify the expression of IL-1 beta, TNF-alpha, TGF-beta, and bFGF in these bone samples.. At the time of the second bone biopsy, the mean serum total alkaline phosphatase activity was normal, whereas mean serum intact parathyroid hormone (iPTH) level was slightly above the upper limit of normal values. Histomorphometric analysis showed a decrease in resorption parameters and static bone formation parameters after PTX. Dynamically, mineral apposition rate (MAR) and mineralization surface (MS/BS) decreased significantly. There was a marked local expression of IL-1beta, TNF-alpha, TGF-beta, and bFGF in bone biopsies before PTX, particularly in fibrous tissue and resorption areas. One year after PTX, IL-1beta decreased from 23.6 +/- 7.5% to 9.9 +/- 3.1%, TNF-alpha from 4.5 +/- 1.5% to 0.7 +/- 0.8%, TGF-beta from 49.6 +/- 9.8% to 15.2 +/- 4.6%, and bFGF from 50.9 +/- 12.7% to 12.9 +/- 7.9% (P < 0.001). A significant correlation was documented between cytokines and growth factors expression in bone with iPTH levels before and after PTX (P < 0.05).. Based on these results, we suggest that IL-1beta, TNF-alpha, TGF-beta, and bFGF are involved in bone remodeling regulation, acting as local effectors, possibly under the control of PTH.

Topics: Adolescent; Adult; Biopsy; Bone and Bones; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Fibroblast Growth Factor 2; Humans; Immunohistochemistry; Interleukin-1; Male; Middle Aged; Parathyroidectomy; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Uremia

The secondary hyperparathyroidism of chronic kidney disease (CKD) produces a high turnover osteodystrophy that is associated with peritrabecular fibrosis. The nature of the cells involved in the development of peritrabecular fibrosis may represent osteoprogenitors expressing a fibroblastic phenotype that are retarded from progressing through osteoblast differentiation.. To test the hypothesis that osteoblast differentiation is retarded in secondary hyperparathyroidism due to CKD producing bone marrow fibrosis, we administered bone morphogenetic protein 7 (BMP-7), a physiologic regulator of osteoblast regulation, to C57BL6 mice that had CKD produced by electrocautery of one kidney followed by contralateral nephrectomy two weeks later. Following the second surgical procedure, a subgroup of mice received daily intraperitoneal injections of BMP-7 (10 microg/kg). Three to six weeks later, the animals were sacrificed, blood was obtained for measurements of blood urea nitrogen (BUN) and parathyroid hormone (PTH) levels, and the femora and tibiae were processed for histomorphometric analysis.. The animals had significant renal insufficiency with BUN values of 77.79 +/- 22.68 mg/dL, and the level of renal impairment between the CKD untreated mice and the CKD mice treated with BMP-7 was the same in the two groups. PTH levels averaged 81.13 +/- 51.36 and 75.4 +/- 43.61 pg/mL in the CKD and BMP-7 treated groups, respectively. The animals with CKD developed significant peritrabecular fibrosis. In addition, there was an increase in osteoblast surface and osteoid accumulation as well as increased activation frequency and increased osteoclast surface consistent with high turnover renal osteodystrophy. Treatment with BMP-7 eliminated peritrabecular fibrosis, increased osteoblast number, osteoblast surface, mineralizing surface and single labeled surface. There was also a significant decrease in the eroded surface induced by treatment with BMP-7.. These findings indicate that BMP-7 treatment in the setting of high turnover renal osteodystrophy prevents the development of peritrabecular fibrosis, affects the osteoblast phenotype and mineralizing surfaces, and decreases bone resorption. This is compatible with a role of osteoblast differentiation in the pathophysiology of osteitis fibrosa.

Topics: Animals; Blood Urea Nitrogen; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Chronic Kidney Disease-Mineral and Bone Disorder; Fibrosis; Hyperparathyroidism, Secondary; Male; Mice; Mice, Inbred C57BL; Renal Insufficiency; Transforming Growth Factor beta

We evaluated the intraplatelet and plasma levels of transforming growth factor beta (TGF-beta) in patients with or without renal osteodystrophy (ROD) who were undergoing hemodialysis (HD). Intraplatelet and plasma levels of TGF-beta were examined before and after HD, and compared with those from healthy controls. Patients undergoing HD had significantly higher mean intraplatelet levels of TGF-beta before and after HD than did the healthy subjects (22.7 +/- 7.8 and 29.5 +/- 15.8 vs. 18.7 +/- 7.9 ng/10(5) platelets; p < .05). The mean intraplatelet and plasma levels of TGF-beta in patients after HD were significantly increased than those before HD and in healthy subjects (p < .05). Moreover, patients with ROD showed a significantly higher mean intraplatelet and plasma levels of TGF-beta than that without ROD (p < .05). To investigate the effects of TGF-beta on ROD in HD patients, we evaluated such parameters as parathyroid hormone (PTH) and alkaline phosphatase (ALP), which reflect the lesions of ROD. The mean intraplatelet level of TGF-beta was not correlated with either para-meter. Meanwhile, no correlation was observed between the intraplatelet level of TGF-beta and the hematocrit (Hct). Similarly, no correlation was observed between the intraplatelet levels of TGF-beta and the dose of erythropoietin (EPO) administered. These findings indicate that metabolism of TGF-beta occurs during HD and overproduction of TGF-beta may play an important role in the pathogenesis of ROD.

Topics: Blood Platelets; Case-Control Studies; Chronic Kidney Disease-Mineral and Bone Disorder; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Transforming Growth Factor beta