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2.
Bone ; 82: 101-7, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26211996

ABSTRACT

Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by µCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p<0.0001, for all) while cortical porosity was increased (p<0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p<0.001 for all). Significant increases in PTH (p<0.0001), RatLAPs (p=0.0002), and urine calcium concentration (p<0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with adverse effects on the trabecular compartment of bone.


Subject(s)
Blood Glucose/drug effects , Bone Diseases/drug therapy , Canagliflozin/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Sodium-Glucose Transporter 2 Inhibitors , Animals , Blood Glucose/metabolism , Bone Diseases/metabolism , Bone Diseases/prevention & control , Canagliflozin/pharmacology , Diabetes Mellitus, Experimental/metabolism , Male , Mice , Mice, Inbred DBA , Sodium-Glucose Transporter 2/metabolism
3.
Bone Rep ; 1: 16-19, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25685827

ABSTRACT

In type 1 diabetes, diabetic bone disease (DBD) is characterized by decreased bone mineral density, a state of low bone turnover and an increased risk of fracture. Animal models of DBD demonstrate that acquired alterations in trabecular and cortical bone microarchitecture contribute to decreased bone strength in diabetes. With anti-collagenolytic and anti-inflammatory properties, tetracycline derivatives may prevent diabetes-related decreases in bone strength. To determine if doxycycline, a tetracycline class antibiotic, can prevent the development of DBD in a model of long-term diabetes, male DBA/2J mice, with or without diabetes, were treated with doxycycline-containing chow for 10 weeks (dose range, 28-92 mg/kg/day). Long-term doxycycline exposure was not deleterious to the microarchitecture or biomechanical properties of healthy bone in male DBA/2J mice. Doxycycline treatment also did not prevent or alleviate the deleterious changes in trabecular microarchitecture, cortical structure, and biomechanical properties of bone induced by chronic diabetes.

4.
Bone ; 57(1): 36-40, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23886838

ABSTRACT

OBJECTIVE: Using a streptozotocin (STZ)-induced mouse model of type 1 diabetes (T1D), we have previously demonstrated that long-term diabetes inhibits regenerative bone formation during tibial distraction osteogenesis (DO) and perturbs skeletal integrity by decreasing cortical thickness, bone mineral density and bone's resistance to fracture. Because long-standing T1D is also associated with a deficiency of insulin-like growth factor I (IGF-I), we examined the effects of systemic IGF-I treatment on skeletal microarchitecture and strength, as well as on bone formation in diabetic mice. RESEARCH DESIGN AND METHODS: Streptozotocin-induced diabetic or control mice were treated with recombinant human IGF-I (rhIGF-I, 1.5mg/kg/day as subcutaneous infusion) or vehicle throughout a 14day DO procedure. Thereafter, trunk blood was assayed for glucose, insulin, rhIGF-I, mouse IGF-I and leptin. Bone formation in distracted tibiae was quantified. Effects on cortical bone strength and trabecular bone architecture were assessed by µCT analysis and three-point bend testing of contralateral femurs. RESULTS: New bone formation during DO was reduced in diabetic mice but significantly improved with rhIGF-I treatment. The contralateral femurs of diabetic mice demonstrated significant reductions in trabecular thickness, yield strength and peak force of cortical bone, which were improved with rhIGF-I treatment. rhIGF-I also reduced intracortical porosity in control mice. However, treatment with rhIGF-I did not normalize serum glucose, or correct concurrent deficiencies of insulin or leptin seen in diabetes. CONCLUSIONS: These findings demonstrate that despite persistent hyperglycemia, rhIGF-I promoted new bone formation and improved biomechanical properties of bone in a model of T1D, suggesting that it may be useful as a fracture preventative in this disease.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Insulin-Like Growth Factor I/therapeutic use , Animals , Hyperglycemia/drug therapy , Mice , Osteogenesis/drug effects
5.
Exp Diabetes Res ; 2011: 269378, 2011.
Article in English | MEDLINE | ID: mdl-21747824

ABSTRACT

Microalbuminuria in humans with Type 1 diabetes (T1D) is associated with increased urinary excretion of megalin, as well as many megalin ligands, including vitamin-D-binding protein (VDBP). We examined the DBA/2J diabetic mouse, nephropathy prone model, to determine if megalin and VDBP excretion coincide with the development of diabetic nephropathy. Megalin, VDBP, and 25-hydroxy-vitamin D (25-OHD) were measured in urine, and genes involved in vitamin D metabolism were assessed in renal tissues from diabetic and control mice at 10, 15, and 18 weeks following the onset of diabetes. Megalin, VDBP, and 25-OHD were increased in the urine of diabetic mice. 1-α hydroxylase (CYP27B1) mRNA in the kidney was persistently increased in diabetic mice, as were several vitamin D-target genes. These studies show that intrarenal vitamin D handling is altered in the diabetic kidney, and they suggest that in T1D, urinary losses of VDBP may portend risk for intrarenal and extrarenal vitamin D deficiencies.


Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/metabolism , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Endocytosis , Vitamin D/metabolism , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/pathology , Disease Models, Animal , Disease Susceptibility , Endocytosis/physiology , Kidney/metabolism , Kidney/pathology , Low Density Lipoprotein Receptor-Related Protein-2/genetics , Low Density Lipoprotein Receptor-Related Protein-2/metabolism , Mice , Mice, Inbred DBA , Signal Transduction/physiology , Streptozocin
6.
J Clin Endocrinol Metab ; 96(1): 142-9, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20943786

ABSTRACT

CONTEXT: Vitamin D deficiency is an increasingly recognized comorbidity in patients with both type 1 (T1D) and type 2 diabetes, particularly associated with the presence of diabetic nephropathy. OBJECTIVE: Because we have previously reported enhanced excretion of megalin in the urine of T1D patients with microalbuminuria, we hypothesized that concurrent urinary loss of the megalin ligand, vitamin D binding protein, might contribute mechanistically to vitamin D deficiency. DESIGN AND PARTICIPANTS: Examining a study cohort of 115 subjects with T1D, aged 14-40 yr, along with 55 age-matched healthy control subjects, we measured plasma and urine concentrations of vitamin D binding protein (VDBP) along with serum concentrations of total calcium, parathyroid hormone, 25-hydroxyvitamin D, and 1, 25-dihydroxyvitamin D; these results were compared between groups and investigated for relationships with metabolic control status or with albuminuria. MAIN OUTCOME MEASURE: Between-group differences in urinary VDBP concentration were the main outcome measures. RESULTS: A marked increase in the urinary excretion of VDBP was apparent in subjects with T1D, compared with control subjects. Using multivariate regression modeling, significant correlates of urinary VDBP excretion included microalbuminuria (P = 0.004), glycosylated hemoglobin (P = 0.010), continuous glucose monitoring system average capillary glucose (P = 0.047), and serum 1,25(OH)(2)D concentrations (P = 0.037). Vitamin D deficiency or insufficiency was slightly more prevalent in diabetic subjects with albuminuria, coincident with the increase in urine VDBP excretion. CONCLUSIONS: These findings suggest that, theoretically, exaggerated urinary loss of VDBP in T1D, particularly in persons with albuminuria, could contribute mechanistically to vitamin D deficiency in this disease.


Subject(s)
Diabetes Mellitus, Type 1/metabolism , Vitamin D Deficiency/metabolism , Vitamin D-Binding Protein/metabolism , Adolescent , Adult , Blood Glucose/metabolism , Calcium/blood , Diabetes Mellitus, Type 1/complications , Female , Humans , Male , Parathyroid Hormone/blood , Regression Analysis , Vitamin D/analogs & derivatives , Vitamin D/blood , Vitamin D Deficiency/complications
7.
Bone ; 48(4): 733-40, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21185416

ABSTRACT

Type 1 diabetes (T1DM) increases the likelihood of a fracture. Despite serious complications in the healing of fractures among those with diabetes, the underlying causes are not delineated for the effect of diabetes on the fracture resistance of bone. Therefore, in a mouse model of T1DM, we have investigated the possibility that a prolonged state of diabetes perturbs the relationship between bone strength and structure (i.e., affects tissue properties). At 10, 15, and 18 weeks following injection of streptozotocin to induce diabetes, diabetic male mice and age-matched controls were examined for measures of skeletal integrity. We assessed 1) the moment of inertia (I(MIN)) of the cortical bone within diaphysis, trabecular bone architecture of the metaphysis, and mineralization density of the tissue (TMD) for each compartment of the femur by micro-computed tomography and 2) biomechanical properties by three-point bending test (femur) and nanoindentation (tibia). In the metaphysis, a significant decrease in trabecular bone volume fraction and trabecular TMD was apparent after 10 weeks of diabetes. For cortical bone, type 1 diabetes was associated with decreased cortical TMD, I(MIN), rigidity, and peak moment as well as a lack of normal age-related increases in the biomechanical properties. However, there were only modest differences in material properties between diabetic and normal mice at both whole bone and tissue-levels. As the duration of diabetes increased, bone toughness decreased relative to control. If the sole effect of diabetes on bone strength was due to a reduction in bone size, then I(MIN) would be the only significant variable explaining the variance in the maximum moment. However, general linear modeling found that the relationship between peak moment and I(MIN) depended on whether the bone was from a diabetic mouse and the duration of diabetes. Thus, these findings suggest that the elevated fracture risk among diabetics is impacted by complex changes in tissue properties that ultimately reduce the fracture resistance of bone.


Subject(s)
Bone and Bones/physiopathology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/physiopathology , Animals , Bone Density , Diabetes Mellitus, Experimental/chemically induced , Male , Mice , Mice, Inbred DBA , Streptozocin , Tomography, X-Ray Computed
8.
Cardiovasc Diabetol ; 9: 73, 2010 Nov 05.
Article in English | MEDLINE | ID: mdl-21054880

ABSTRACT

BACKGROUND: Insulin resistance is associated with a proinflammatory state that promotes the development of complications such as type 2 diabetes mellitus (T2DM) and atherosclerosis. The metabolic stimuli that initiate and propagate proinflammatory cytokine production and the cellular origin of proinflammatory cytokines in insulin resistance have not been fully elucidated. Circulating proinflammatory monocytes show signs of enhanced inflammation in obese, insulin resistant subjects and are thus a potential source of proinflammatory cytokine production. The specific, circulating metabolic factors that might stimulate monocyte inflammation in insulin resistant subjects are poorly characterized. We have examined whether saturated nonesterified fatty acids (NEFA) and insulin, which increase in concentration with developing insulin resistance, can trigger the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in human monocytes. METHODS: Messenger RNA and protein levels of the proinflammatory cytokines IL-6 and TNF-α were measured by quantitative real-time PCR (qRT-PCR) and Luminex bioassays. Student's t-test was used with a significance level of p < 0.05 to determine significance between treatment groups. RESULTS: Esterification of palmitate with coenzyme A (CoA) was necessary, while ß-oxidation and ceramide biosynthesis were not required, for the induction of IL-6 and TNF-α in THP-1 monocytes. Monocytes incubated with insulin and palmitate together produced more IL-6 mRNA and protein, and more TNF-α protein, compared to monocytes incubated with palmitate alone. Incubation of monocytes with insulin alone did not affect the production of IL-6 or TNF-α. Both PI3K-Akt and MEK/ERK signalling pathways are important for cytokine induction by palmitate. MEK/ERK signalling is necessary for synergistic induction of IL-6 by palmitate and insulin. CONCLUSIONS: High levels of saturated NEFA, such as palmitate, when combined with hyperinsulinemia, may activate human monocytes to produce proinflammatory cytokines and support the development and propagation of the subacute, chronic inflammatory state that is characteristic of insulin resistance. Results with inhibitors of ß-oxidation and ceramide biosynthesis pathways suggest that increased fatty acid flux through the glycerolipid biosynthesis pathway may be involved in promoting proinflammatory cytokine production in monocytes.


Subject(s)
Fatty Acids, Nonesterified/metabolism , Inflammation Mediators/metabolism , Insulin/metabolism , Interleukin-6/metabolism , Monocytes/metabolism , Palmitic Acid/metabolism , Cell Line, Tumor , Ceramides/biosynthesis , Coenzyme A/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Insulin Resistance , Interleukin-6/genetics , MAP Kinase Kinase Kinases/metabolism , Monocytes/immunology , Oxidation-Reduction , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/metabolism , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation
9.
Endocrine ; 37(2): 336-43, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20960272

ABSTRACT

Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal injury, can bind matrix metalloproteinase-9 (MMP-9) and inhibit its degradation, thereby sustaining MMP-9 proteolytic activity. MMP-9 is produced by renal podocytes, and podocyte MMP production can be modified by high ambient glucose levels. Moreover, dysregulation of MMP-9 activity, gene expression, or urine concentrations has been demonstrated in T2DM-associated nephropathy and in non-diabetic proteinuric renal diseases. Our objective was to determine whether NGAL/MMP-9 dysregulation might contribute to or serve as a biomarker of diabetic nephropathy in type 1 DM (T1DM). Plasma MMP-9, and urine NGAL and MMP-9 concentrations were measured in 121 T1DM and 55 control subjects and examined relative to indicators of glycemia, renal function, and degree of albuminuria. T1DM was associated with a significant increase in urinary excretion of both NGAL and MMP-9, and urine NGAL:Cr (NGAL corrected to urine creatinine) and urine MMP-9:Cr concentrations were highly correlated with each other. Both were also positively correlated with measurements of glycemic control and with albuminuria. Plasma MMP-9, urine MMP-9, and urine NGAL concentrations were significantly higher in females compared to males, and urine MMP-9:Cr concentrations displayed a menstrual cycle specific pattern. Increased urinary excretion of NGAL and MMP-9 supports a role for NGAL/MMP-9 dysregulation in renal dysfunction; moreover, gender-specific differences could support a gender contribution to pathological mechanisms or susceptibility for the development of renal complications in diabetes mellitus.


Subject(s)
Acute-Phase Proteins/urine , Diabetes Mellitus, Type 1/metabolism , Diabetic Nephropathies/metabolism , Lipocalins/urine , Matrix Metalloproteinase 9/urine , Proto-Oncogene Proteins/urine , Sex Characteristics , Acute-Phase Proteins/genetics , Adolescent , Adult , Age Factors , Albuminuria/metabolism , Albuminuria/physiopathology , Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/physiopathology , Female , Gene Expression/physiology , Humans , Kidney Function Tests , Lipocalin-2 , Lipocalins/genetics , Male , Matrix Metalloproteinase 9/blood , Matrix Metalloproteinase 9/genetics , Podocytes/physiology , Proto-Oncogene Proteins/genetics , Tissue Inhibitor of Metalloproteinase-1/blood , Young Adult
10.
Bone ; 46(2): 410-7, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19772956

ABSTRACT

Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-alpha (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediated through TNF receptor 1 and/or 2 (TNFR1/2) signaling. We utilized a unique model of mouse DO to assess the effects of 1) TNFR homozygous null gene alterations on direct bone formation and 2) rmTNF on wild type (WT), TNFR1(-/-) (R1KO), and TNR2(-/-) (R2KO) mice. Radiological and histological analyses of direct bone formation in the distraction gaps demonstrated no significant differences between the WT, R1KO, R2KO, or TNFR1(-/-) and R2(-/-) (R1 and 2KO) mice. R1 and 2KO mice had elevated levels of serum TNF but demonstrated no inhibition of new bone formation. Systemic administration by osmotic pump of rmTNF during DO (10 microg/kg/day) resulted in significant inhibition of gap bone formation measures in WT and R2KO mice, but not in R1KO mice. We conclude that exogenous rmTNF and/or endogenous TNF act to inhibit new bone formation during DO by signaling primarily through TNFR1.


Subject(s)
Osteogenesis, Distraction , Osteogenesis/physiology , Receptors, Tumor Necrosis Factor, Type II/metabolism , Receptors, Tumor Necrosis Factor, Type I/deficiency , Tumor Necrosis Factor-alpha/pharmacology , Animals , Bone and Bones/diagnostic imaging , Bone and Bones/drug effects , Bone and Bones/pathology , Male , Mice , Osteogenesis/drug effects , Radiography , Receptors, Tumor Necrosis Factor, Type I/metabolism , Recombinant Proteins/pharmacology , Staining and Labeling , Tumor Necrosis Factor-alpha/blood
11.
J Bone Miner Res ; 25(1): 114-23, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19580462

ABSTRACT

Skeletal changes accompanying aging are associated with both increased risk of fractures and impaired fracture healing, which, in turn, is due to compromised bone regeneration potential. These changes are associated with increased serum levels of selected proinflammatory cytokines, e.g., tumor necrosis factor alpha (TNF-alpha). We have used a unique model of bone regeneration to demonstrate (1) that aged-related deficits in direct bone formation can be restored to young mice by treatment with TNF blockers and (2) that the cyclin-dependent kinase inhibitor p21 is a candidate for mediation of the osteoinhibitory effects of TNF. It has been hypothesized recently that TNF antagonists may represent novel anabolic agents, and we believe that the data presented here represent a successful test of this hypothesis.


Subject(s)
Aging/drug effects , Osteoblasts/cytology , Osteoblasts/drug effects , Osteogenesis/drug effects , Regeneration/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Aging/blood , Animals , Blotting, Western , Cyclin-Dependent Kinase Inhibitor p21/deficiency , Cytokines/blood , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Radiography , Receptors, Tumor Necrosis Factor, Type I/pharmacology , Receptors, Tumor Necrosis Factor, Type II/pharmacology , Recombinant Proteins/pharmacology , Solubility/drug effects , Tibia/diagnostic imaging , Tibia/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Wound Healing/drug effects
12.
Diabetes Care ; 32(7): 1266-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19366958

ABSTRACT

OBJECTIVE: Proteinuria is the hallmark of diabetic nephropathy; yet, glomerular histology does not fully explain mechanisms contributing to proteinuria. Our objective was to identify proteins in the urine of individuals with type 1 diabetes and microalbuminuria that might implicate a mechanistic pathway operative in proteinuria. RESEARCH DESIGN AND METHODS: Using a GeLC/MS platform proteomics approach, we compared the urine proteome from 12 healthy nondiabetic individuals, 12 subjects with type 1 diabetes yet normal urinary albumin excretion rates, and 12 subjects with type 1 diabetes and microalbuminuria (type 1 diabetes + microalbuminuria). RESULTS: The abundance of megalin and cubilin, two multiligand receptors expressed in kidney proximal tubule cells and involved with the reuptake of filtered albumin and megalin/cubilin ligands, was significantly increased in type 1 diabetes + microalbuminuria urine, compared with both nonalbuminuric groups. CONCLUSIONS: Aberrant shedding of megalin and cubilin could contribute to albuminuria in diabetes and to deficiency states of important vitamins and hormones.


Subject(s)
Adaptor Proteins, Signal Transducing/urine , Albuminuria/etiology , Diabetes Mellitus, Type 1/urine , Receptors, Cell Surface/metabolism , Albuminuria/epidemiology , Albuminuria/urine , Blood Pressure , Diabetic Nephropathies/urine , Female , Glomerular Filtration Rate , Humans , Low Density Lipoprotein Receptor-Related Protein-2 , Male , Proteomics/methods , Reference Values
13.
Endocrinology ; 149(4): 1697-704, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18162513

ABSTRACT

Type 1 diabetes mellitus is associated with a number of disorders of skeletal health, conditions that rely, in part, on dynamic bone formation. A mouse model of distraction osteogenesis was used to study the consequences of streptozotocin-induced diabetes and insulin treatment on bone formation and osteoblastogenesis. In diabetic mice compared with control mice, new bone formation was decreased, and adipogenesis was increased in and around, respectively, the distraction gaps. Although insulin treatment restored bone formation to levels observed in nondiabetic control mice, it failed to significantly decrease adipogenesis. Molecular events altered during de novo bone formation in untreated type 1 diabetes mellitus, yet restored with insulin treatment were examined so as to clarify specific osteogenic genes that may contribute to diabetic bone disease. RNA from distraction gaps was analyzed by gene microarray and quantitative RT-PCR for osteogenic genes of interest. Runt-related transcription factor 2 (RUNX2), and several RUNX2 target genes, including matrix metalloproteinase-9, Akp2, integrin binding sialoprotein, Dmp1, Col1a2, Phex, Vdr, osteocalcin, and osterix, were all significantly down-regulated in the insulin-deficient, hyperglycemic diabetic animals; however, insulin treatment of diabetic animals significantly restored their expression. Expression of bone morphogenic protein-2, transcriptional coactivator with PDZ-binding motif, and TWIST2, all important regulators of RUNX2, were not impacted by the diabetic condition, suggesting that the defect in osteogenesis resides at the level of RUNX2 expression and its activity. Together, these data demonstrate that insulin and/or glycemic status can regulate osteogenesis in vivo, and systemic insulin therapy can, in large part, rescue the diabetic bone phenotype at the tissue and molecular level.


Subject(s)
Core Binding Factor Alpha 1 Subunit/genetics , Diabetes Mellitus, Type 1/physiopathology , Osteogenesis/physiology , Animals , Bone Morphogenetic Protein 2 , Bone Morphogenetic Proteins/genetics , Core Binding Factor Alpha 1 Subunit/physiology , Down-Regulation , Female , Insulin/pharmacology , Matrix Metalloproteinase 9/genetics , Mice , Osteogenesis, Distraction , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta/genetics
14.
Diabetes Care ; 30(9): 2321-6, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17563344

ABSTRACT

OBJECTIVE: Dysregulation of matrix metalloproteinase (MMP)-2 may contribute pathologically to the development of diabetes complications, including diabetic retinopathy and coronary and peripheral arterial disease. Our objective was to explore whether systemic MMP-2 dysregulation could be demonstrated in type 1 diabetes and to determine how MMP-2 concentration relates to disease status. RESEARCH DESIGN AND METHODS: In this cross-sectional study, MMP-2 concentrations and MMP-2 activity were measured in plasma and timed urine samples from 93 type 1 diabetic and 50 healthy control subjects, aged 14-40 years. Relationships between MMP-2 concentrations in these biological fluids and subject characteristics (sex, age, and duration of type 1 diabetes), indexes of glycemic control (A1C, fasting plasma glucose, and continuous glucose monitoring system average daily glucose), and measurements of renal function (urinary albumin excretion and glomerular filtration rate) were examined. RESULTS: Urine and plasma MMP-2 concentrations and plasma MMP-2 activity were all significantly elevated in type 1 diabetic subjects compared with those in control subjects. Urine MMP-2 concentrations, in particular, were correlated with several clinical parameters that infer increased risk for diabetic comorbidity and specifically for diabetic nephropathy, including higher A1C, longer duration of disease, evidence of renal hyperfiltration, and the presence of microalbuminuria. CONCLUSIONS: Urine and plasma MMP-2 concentrations are dysregulated in type 1 diabetes; urinary excretion of MMP-2, in particular, might provide a unique biomarker of diabetes-induced intrarenal pathologic processes.


Subject(s)
Diabetes Complications/etiology , Diabetes Mellitus, Type 1/metabolism , Matrix Metalloproteinase 2/metabolism , Adolescent , Adult , Cross-Sectional Studies , Diabetes Complications/metabolism , Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/etiology , Female , Humans , Male , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 2/urine
15.
Acta Orthop ; 78(1): 46-55, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17453392

ABSTRACT

BACKGROUND: There is evidence to suggest that impairment in bone formation and/or turnover is associated with the metabolic abnormalities characteristic of type-2 diabetes mellitus. However, bone regeneration/repair in type-2 diabetes has not been modeled. Using Zucker Diabetic Fatty (ZDF) rats (a model of type-2 diabetes) for tibial distraction osteogenesis (DO), we hypothesized that bone formation within the distraction gap would be impaired. ANIMALS AND METHODS: Rats were examined for body weight, glycosuria, and glycosemia to confirm the diabetic condition during the study. The rats received placement of the external fixators and osteotomies on the left tibia. Distraction was initiated the following day at 0.2 mm twice a day and continued for 14 days. The lengthened tibiae were harvested and distraction gaps were examined radiographically and histologically. RESULTS: We found significant reduction in new bone formation in the distraction gaps of the ZDF rats, both radiographically and histologically, compared to lean rats. We found a decrease in a marker of cellular proliferation in the distraction gaps and increased adipose volume in adjacent bone marrow of the ZDF rats. INTERPRETATION: Our findings suggest that this model might be used to study the contributions of leptin resistance, insulin resistance and/or hyperglycemia to impaired osteoblastogenesis in vivo.


Subject(s)
Bone Regeneration/physiology , Bone and Bones/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Osteogenesis/physiology , Animals , Bone Density , Bone and Bones/cytology , Bone and Bones/pathology , Cell Proliferation , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Immunohistochemistry , Models, Biological , Rats , Rats, Zucker , Tibia/cytology , Tibia/metabolism , Tibia/pathology
16.
J Bone Miner Res ; 21(9): 1359-66, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16939394

ABSTRACT

UNLABELLED: DO was used in an aged mouse model to determine if systemically and/or locally administered rhIGF-I improved osteoblastogenesis and new bone formation. Local and systemic rhIGF-I treatment increased new bone formation. However, only systemic delivery produced measurable concentrations of rhIGF-I in the circulation. INTRODUCTION: Human and rodent research supports a primary role for IGF-I in bone formation. Significant roles for both endocrine and paracrine/autocrine IGF-I have been suggested for normal osteoblastogenesis and bone formation. We have assessed, using a mouse model of distraction osteogenesis (DO), the impact of continuous administration of recombinant human (rh)IGF-I, delivered either locally to the distraction site or absorbed systemically, on bone formation in an aged mouse model. MATERIALS AND METHODS: DO was performed in aged mice (18-month-old C57BL/6 male mice), which were distracted at 0.15 mm daily. At the time of osteotomy, miniosmotic pumps were inserted subcutaneously to (1) deliver vehicle or rhIGF-I subcutaneously for systemic delivery or (2) deliver vehicle or rhIGF-I directly to the newly forming bone through infusion tubing routed subcutaneously from the pump to the distraction site. Serum concentrations of mouse IGF-I, human IGF-I, and osteocalcin were determined at the end of the study. RESULTS: New bone formation observed in DO gaps showed a significant increase in new bone formation in rhIGF-I-treated mice, irrespective of delivery route. However, detectable levels of human IGF-I were found only in the serum of animals receiving rhIGF-I systemically. Osteocalcin levels did not differ between controls and rhIGF-I-treated groups. CONCLUSIONS: Locally and systemically delivered rhIGF-I both produce significant increases in new bone formed in an aged mouse model in which new bone formation is normally markedly impaired, suggesting that rhIGF-I may improve senile osteoporosis. Because systemic administration of IGF-I can result in untoward side effects, including an increased risk for cancer, the findings that locally delivered IGF-I improves bone regeneration without increasing circulating IGF-I levels suggests that this delivery route may be preferable in an at-risk, aged population.


Subject(s)
Aging/drug effects , Injections, Intralesional/methods , Insulin-Like Growth Factor I/administration & dosage , Osteogenesis/drug effects , Recombinant Proteins/administration & dosage , Animals , Electron Probe Microanalysis , Humans , Injections, Intralesional/instrumentation , Male , Mice , Mice, Inbred C57BL , Models, Animal , Models, Biological , Osteotomy/rehabilitation , Radiography , Tibia/cytology , Tibia/diagnostic imaging
17.
Diabetes ; 54(10): 2875-81, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16186388

ABSTRACT

The effects of type 1 diabetes on de novo bone formation during tibial distraction osteogenesis (DO) and on intact trabecular and cortical bone were studied using nonobese diabetic (NOD) mice and comparably aged nondiabetic NOD mice. Diabetic mice received treatment with insulin, vehicle, or no treatment during a 14-day DO procedure. Distracted tibiae were analyzed radiographically, histologically, and by microcomputed tomography (microCT). Contralateral tibiae were analyzed using microCT. Serum levels of insulin, osteocalcin, and cross-linked C-telopeptide of type I collagen were measured. Total new bone in the DO gap was reduced histologically (P < or = 0.001) and radiographically (P < or = 0.05) in diabetic mice compared with nondiabetic mice but preserved by insulin treatment. Serum osteocalcin concentrations were also reduced in diabetic mice (P < or = 0.001) and normalized with insulin treatment. Evaluation of the contralateral tibiae by microCT and mechanical testing demonstrated reductions in trabecular bone volume and thickness, cortical thickness, cortical strength, and an increase in endosteal perimeter in diabetic animals, which were prevented by insulin treatment. These studies demonstrate that bone formation during DO is impaired in a model of type 1 diabetes and preserved by systemic insulin administration.


Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Osteogenesis/physiology , Animals , Bone and Bones/chemistry , Collagen/blood , Collagen Type I , Diabetes Mellitus, Type 1/drug therapy , Female , Immunohistochemistry , Insulin/blood , Insulin/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Osteocalcin/blood , Osteogenesis/drug effects , Osteogenesis, Distraction , Peptides/blood , Receptor, Insulin/analysis , Tibia/chemistry , Tomography, X-Ray Computed
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