Amelioration of type I diabetes‐induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival

Type 1 diabetic osteoporosis results from impaired osteoblast activity and death. Therefore, anti‐resorptive treatments may not effectively treat bone loss in this patient population. Intermittent parathyroid hormone (PTH) treatment stimulates bone remodeling and increases bone density in healthy subjects. However, PTH effects may be limited in patients with diseases that interfere with its signaling. Here, we examined the ability of 8 and 40 µg/kg intermittent PTH to counteract diabetic bone loss. PTH treatment reduced fat pad mass and blood glucose levels in non‐diabetic PTH‐treated mice, consistent with PTH‐affecting glucose homeostasis. However, PTH treatment did not significantly affect general body parameters, including the blood glucose levels, of type 1 diabetic mice. We found that the high dose of PTH significantly increased tibial trabecular bone density parameters in control and diabetic mice, and the lower dose elevated trabecular bone parameters in diabetic mice. The increased bone density was due to increased mineral apposition and osteoblast surface, all of which are defective in type 1 diabetes. PTH treatment suppressed osteoblast apoptosis in diabetic bone, which could further contribute to the bone‐enhancing effects. In addition, PTH treatment (40 µg/kg) reversed preexisting bone loss from diabetes. We conclude that intermittent PTH may increase type 1 diabetic trabecular bone volume through its anabolic effects on osteoblasts. J. Cell. Physiol. 227: 1326–1334, 2012. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90247/1/22844_ftp.pd

Needle loss in subclavian vein during central venous catheter placement: Case report of a rare complication

We present a case of needle separation during central venous catheter (CVC) placement in a super morbidly obese patient with subsequent surgical intervention in its retrieval. This complication, potentially lethal due to the relevant anatomy of such a procedure, alerts critical care physicians and surgeons to the possibility of equipment failure and stresses proper technique in what has become a routine procedure. It also emphasizes the routine use of ultrasound-guidance for cannulation in patients of any body habitus. While infection and arrhythmia are the generally known complications of CVC placement, clinicians must be alert to unanticipated events such as needle separation. In our case, the retrieval of this needle required multi-disciplinary intervention between radiology, critical care, vascular surgery, and thoracic surgery. Our event stresses hypervigilance to complications in a common procedure

Deficits in trabecular bone microarchitecture in young women with Type 1 diabetes mellitus

Context: The pathophysiological mechanism of increased fractures in young adults with Type 1 Diabetes Mellitus (T1DM) is unclear. Objective: Case:control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Patients and Settings: 30 women with T1DM with a median (range) age of 22.0yrs (16.9, 36.1) attending one outpatient clinic with a median age at diagnosis of 9.7yrs (0.46, 14.8) were compared to 28 age-matched healthy women who acted as controls. Methods and Main Outcome Measures: Measurements included MRI-based assessment of proximal tibial bone volume/total volume (appBV/TV), trabecular separation (appTb.Sp), vertebral bone marrow adiposity (BMA) and abdominal adipose tissue and biochemical markers of GH/IGF-1 axis (IGF-1, IGFBP3, ALS) and bone turnover. Results: Median appBV/TV in cases and controls was 0.3 (0.22, 0.37) and 0.33 (0.26, 0.4), respectively (p = 0.018) and median appTb.Sp in T1DM was 2.59 (2.24, 3.38) and 2.32 (2.03, 2.97), respectively (p = 0.012). The median appBV/TV was 0.28 (0.22, 0.33) in those cases with retinopathy (n,15) compared to 0.33 (0.25, 0.37) in those without retinopathy (p = 0.02). Although median visceral adipose tissue in cases was higher than in controls at 5,733mm3 (2030, 11,144) and 3,460mm3 (1,808, 6,832), respectively (p = 0.012), there was no difference in median BMA which was 31.1% (9.9, 59.9) and 26.3% (8.5, 49.8) in cases and controls, respectively (p = 0.2). Serum IGF-1 and ALS were also lower in cases and the latter showed an inverse association to appTbSp (r = -0.30, p = 0.04). Conclusion: Detailed MRI studies in young women with childhood-onset T1DM have shown clear deficits in trabecular microarchitecture of the tibia. Underlying pathophysiological mechanisms may include a microvasculopathy

Metal concentrations in the blood and tissues after implantation of titanium growth guidance sliding instrumentation

BACKGROUND: Growth guidance sliding treatment devices such as Shilla (Medtronic, USA) or LSZ-4D (Conmet, Russia) used for the treatment of scoliosis in children who have high growth potential have unlocked fixtures allowing rods to slide during growth of the spine which avoids periodical extensions. However, the probability of clinical complications associated with metallosis after the implantation of such devices is poorly understood. The content of metal ions in the blood and tissues of pediatric patients treated for scoliosis using fusionless growth guidance sliding instrumentation, have not yet been investigated. PURPOSE: The aim of this study was to measure the content of metal ions in blood and tissues surrounding implanted growth guidance sliding LSZ-4D devices made of titanium alloy (Ti6Al4V) and to identify the incidence of metallosis associated clinical complications in some patients with these devices. STUDY DESIGN: One center case-control retrospective study. PATIENTS SAMPLE: Study group included 25 patients with high growth potential (3 males, 22 females, average age at primary surgery for scoliosis treatment is 11.4±1.2 years old) who had sliding growth guidance instrumentation LSZ-4D (Conmet, Moscow, Russia) implanted on 13 (range 10-16) spine levels for 6±2 years. The LSZ-4D device was made from titanium alloy Ti6Al4V and consisted of two rectangular section rods and fixture elements. Locked fixtures were used on one spinal level, while the others were unlocked (sliding). The control group consisted of 13 patients (12 females and 1 male, 11±1.2 years old) without any implanted devices. OUTCOME MEASURES: The content of Ti, Al and V metal ions in the whole blood and tissues around the implanted device was measured. Incidence of metallosis associated complications in the study group were recorded. METHODS: Metal ion content was measured by ICP-MC on quadrupolar Nexion 300D (Perkin Elmer, USA). RESULTS: 5 of 25 patients in the study group developed metallosis associated complications (two sinuses and three seromas in the lumbar part of the spine). Revisions were carried out in two of these patients. 90% of patients in the study group had increased content of Ti and V ions in the blood (2.8 and 4 times respectively). Median content of Ti ions in soft tissues adjacent to implanted sliding device was more than 1,500 fold higher compared with the control group. These levels are much higher than previously reported for spinal instrumentation. CONCLUSION: Increased content of Ti and V ions in the blood and especially in tissues around the titanium growth guidance sliding device LSZ-4D accompanied by clinical manifestations (seromas and sinuses) indicate the importance of improving of wear resistance of such instrumentation with the coatings and the necessity to exchange sliding instrumentation once the child is fully grown

Streptozotocin, Type I Diabetes Severity and Bone

As many as 50% of adults with type I (T1) diabetes exhibit bone loss and are at increased risk for fractures. Therapeutic development to prevent bone loss and/or restore lost bone in T1 diabetic patients requires knowledge of the molecular mechanisms accounting for the bone pathology. Because cell culture models alone cannot fully address the systemic/metabolic complexity of T1 diabetes, animal models are critical. A variety of models exist including spontaneous and pharmacologically induced T1 diabetic rodents. In this paper, we discuss the streptozotocin (STZ)-induced T1 diabetic mouse model and examine dose-dependent effects on disease severity and bone. Five daily injections of either 40 or 60 mg/kg STZ induce bone pathologies similar to spontaneously diabetic mouse and rat models and to human T1 diabetic bone pathology. Specifically, bone volume, mineral apposition rate, and osteocalcin serum and tibia messenger RNA levels are decreased. In contrast, bone marrow adiposity and aP2 expression are increased with either dose. However, high-dose STZ caused a more rapid elevation of blood glucose levels and a greater magnitude of change in body mass, fat pad mass, and bone gene expression (osteocalcin, aP2). An increase in cathepsin K and in the ratio of RANKL/OPG was noted in high-dose STZ mice, suggesting the possibility that severe diabetes could increase osteoclast activity, something not seen with lower doses. This may contribute to some of the disparity between existing studies regarding the role of osteoclasts in diabetic bone pathology. Examination of kidney and liver toxicity indicate that the high STZ dose causes some liver inflammation. In summary, the multiple low-dose STZ mouse model exhibits a similar bone phenotype to spontaneous models, has low toxicity, and serves as a useful tool for examining mechanisms of T1 diabetic bone loss

Activation of Hepatic Lipase Expression by Oleic Acid: Possible Involvement of USF1

Polyunsaturated fatty acids affect gene expression mainly through peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element binding proteins (SREBPs), but how monounsaturated fatty acids affect gene expression is poorly understood. In HepG2 cells, oleate supplementation has been shown to increase secretion of hepatic lipase (HL). We hypothesized that oleate affects HL gene expression at the transcriptional level. To test this, we studied the effect of oleate on HL promoter activity using HepG2 cells and the proximal HL promoter region (700 bp). Oleate increased HL expression and promoter activity 1.3–2.1 fold and reduced SREBP activity by 50%. Downregulation of SREBP activity by incubation with cholesterol+25-hydroxycholesterol had no effect on HL promoter activity. Overexpression of SREBP2, but not SREBP1, reduced HL promoter activity, which was effected mainly through the USF1 binding site at -307/-312. Oleate increased the nuclear abundance of USF1 protein 2.7 ± 0.6 fold, while USF1 levels were reduced by SREBP2 overexpression. We conclude that oleate increases HL gene expression via USF1. USF1 may be an additional fatty acid sensor in liver cells

Thermal imprinting modifies bone homeostasis in cold-challenged sea bream (Sparus aurata)

Fish are ectotherms and temperature plays a determinant role in their physiology, biology and ecology, and is a driver of seasonal responses. The present study assessed how thermal imprinting during embryonic and larval stages modified the response of adult fish to low water temperature. We targeted the gilthead sea bream, which develops a condition known as winter syndrome when it is exposed to low water temperatures. Eggs and larvae of sea bream were exposed to four different thermal regimes and then the response of the resulting adults to a low temperature challenge was assessed. Sea bream exposed to a high-low thermal regime as eggs and larvae (HLT; 22 degrees C until hatch and then 18 degrees C until larvae-juvenile transition) had increased plasma cortisol and lower sodium and potassium in response to a cold challenge compared with the other thermal history groups. Plasma glucose and osmolality were increased in cold-challenged HLT fish relative to the unchallenged HLT fish. Cold challenge modified bone homeostasis/responsiveness in the low-high thermal regime group (LHT) relative to other groups, and ocn, ogn1/2, igf1, gr and tr alpha/beta transcripts were all downregulated. In the low temperature group (LT) and HLT group challenged with a low temperature, alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities were decreased relative to unchallenged groups, and bone calcium content also decreased in the LT group. Overall, the results indicate that thermal imprinting during early development of sea bream causes a change in the physiological response of adults to a cold challenge.Seventh Framework Programme project Lifecycle [EU-FP7 222719

Prominent Bone Loss Mediated by RANKL and IL-17 Produced by CD4+ T Cells in TallyHo/JngJ Mice

Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis