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Christian Kasperk,
Andreas Haas,
Jens Hillengass,
Christel Weiss,
Kai Neben,
Hartmut Goldschmidt, Ulrike Sommer,
Peter Nawroth,
Peter-Jürgen Meeder,
Bernd Wiedenhöfer,
Gerhard Schmidmaier,
Michael Tanner,
Dirk Neuhof,
Gerd Nöldge,
Ingo A Grafe
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ABSTRACT: This retrospective study of 73 myeloma patients with painful vertebral lesions compares clinical and radiomorphological outcomes up to 2 years after additional kyphoplasty, radiation therapy or systemic treatment only.
We assessed pain, disability and radiomorphological parameters by visual analogue scale (VAS 0-100), Oswestry Disability Index and by re-evaluating available follow-up X-rays, respectively, in patients that were treated according to a clinical pathway.
After 2 years the VAS score was reduced in all groups by 66 ± 8.2 (kyphoplasty), 35 ± 10.5 (radiation therapy) and 38 ± 20.5 (systemic therapy only). Only after kyphoplasty we observed a significantly reduced Oswestry Disability Index after 1 year (P < 0.001). Vertebral height remained stable after kyphoplasty (P = 0.283), in contrast to a progressive height loss in the other groups (P = 0.013 and P = 0.015 for radiation and systemic therapy only, respectively). Two years after kyphoplasty and radiotherapy the overall vertebral fracture incidence was significantly decreased as compared to the group after systemic therapy only (9.7% of all thoracic and lumbar vertebrae had new vertebral fractures after systemic therapy only, 2% after kyphoplasty (P < 0.001), 4.8% after radiation (P = 0.032)).
Additional kyphoplasty was more effective than additional radiation or systemic therapy in terms of pain relief, reduction of pain associated disability and reduction of fracture incidence of the entire lumbar and thoracic spine.
Journal of Surgical Oncology 09/2011; 105(7):679-86. · 2.10 Impact Factor
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ABSTRACT: Angiogenesis is indispensable during fracture repair, and vascular endothelial growth factor (VEGF) is critical in this process. CCN1 (CYR61) is an extracellular matrix signaling molecule that has been implicated in neovascularization through its interactions with several endothelial integrin receptors. CCN1 has been shown to be up-regulated during the reparative phase of fracture healing; however, the role of CCN1 therein remains unclear. Here, the regulation of CCN1 expression in osteoblasts and the functional consequences thereof were studied. Stimulation of osteoblasts with VEGF resulted in a dose- and time-dependent up-regulation of CCN1 mRNA and protein. An up-regulation of both cell surface-associated CCN1 as well as extracellular matrix-associated CCN1 in osteoblasts was found. The supernatant of VEGF-prestimulated osteoblasts was chemotactic for endothelial cells, increasing their migration and stimulated capillary-like sprout formation. These effects could be attributed to the presence of CCN1 in the osteoblast supernatant as they were prevented by an antibody against CCN1 or by small interfering RNA-mediated knockdown of osteoblast CCN1. Moreover, the supernatant of VEGF-prestimulated osteoblasts induced angiogenesis in Matrigel plugs in vivo in a CCN1-dependent manner. In addition, blockade of CCN1 prevented bone fracture healing in mice. Taken together, the present work demonstrates a potential paracrine loop consisting of the VEGF-mediated up-regulation of CCN1 in osteoblasts that attracts endothelial cells and promotes angiogenesis. Such a loop could be operative during fracture healing.
Journal of Biological Chemistry 10/2007; 282(37):26746-53. · 4.77 Impact Factor
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Christian Kasperk,
Jochen Hillmeier,
Gerd Nöldge,
Ingo A Grafe,
Katharina Dafonseca,
Dorothea Raupp,
Hubert Bardenheuer,
Martin Libicher,
Ute Monika Liegibel, Ulrike Sommer,
Ulrike Hilscher,
Walter Pyerin,
Marcus Vetter,
Hans-Peter Meinzer,
Peter-Jürgen Meeder,
Rod S Taylor,
Peter Nawroth
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ABSTRACT: This study investigates the effects of kyphoplasty on pain and mobility in patients with osteoporosis and painful vertebral fractures compared with conventional medical management.
Pharmacological treatment of patients with primary osteoporosis does not prevent pain and impaired activity of patients with painful vertebral fractures. Therefore, we evaluated the clinical outcome after kyphoplasty in patients with vertebral fractures and associated chronic pain for >12 months.
Sixty patients with primary osteoporosis and painful vertebral fractures presenting for >12 months were included in this prospective, nonrandomized controlled study. Twenty-four hours before performing kyphoplasty, the patients self-determined their inclusion into the kyphoplasty or control group so that 40 patients were treated with kyphoplasty, whereas 20 served as controls. This study assessed changes in radiomorphology, pain visual analog scale (VAS) score, daily activities (European Vertebral Osteoporosis Study [EVOS] score), number of new vertebral fractures, and health care use. Outcomes were assessed before treatment and at 3 and 6 months of follow-up. All patients received standard medical treatment (1g calcium, 1000 IE vitamin D(3), standard dose of oral aminobisphosphonate, pain medication, physical therapy).
Kyphoplasty increased midline vertebral height of the treated vertebral bodies by 12.1%, whereas in the control group, vertebral height decreased by 8.2% (p = 0.001). Augmentation and internal stabilization by kyphoplasty resulted in a reduction of back pain. VAS pain scores improved in the kyphoplasty group from 26.2 +/- 2 to 44.2 +/- 3.3 (SD; p = 0.007) and in the control group from 33.6 +/- 4.1 to 35.6 +/- 4.1 (not significant), whereas the EVOS score increased in the kyphoplasty group from 43.8 +/- 2.4 to 54.5 +/- 2.7 (p = 0.031) and in the control group from 39.8 +/- 4.5 to 43.8 +/- 4.6 (not significant). The number of back pain-related doctor visits within the 6-month follow-up period decreased significantly after kyphoplasty compared with controls: mean of 3.3 visits/patient in the kyphoplasty group and a mean of 8.6 visits/patient in the control group (p = 0.0147).
The results of this study show significantly increased vertebral height, reduced pain, and improved mobility in patients after kyphoplasty. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.
Journal of Bone and Mineral Research 04/2005; 20(4):604-12. · 6.37 Impact Factor
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ABSTRACT: Two isoforms of the androgen receptor (AR-A and AR-B), differing by a lack of the first 187 amino acids in the NH2-terminal transactivation domain of AR-A, are expressed in connective tissue and bone. Transient transfections of normal human osteoblastic cells (HOB) and of genital skin fibroblasts defective in AR (GSF-540) were utilized to compare the functional properties of AR isoforms in mesenchymal tissues. Overexpression of AR-B or AR-A did not significantly affect type I collagen secretion. However, overexpression of AR-B (but not AR-A) restored androgen-dependent DNA synthesis in AR-defective fibroblasts and increased DHT-mediated DNA synthesis three-fold in osteoblastic cells. Overexpression of AR-A did not affect DHT action but reduced DHT-dependent DNA synthesis when transfected together with AR-B. The need for an NH2-terminal sequence of the AR for complete receptor function was demonstrated using electrophoretic mobility shift assay. A peptide coding for the amino terminus of the complete AR was able to decrease the binding affinity of AR-B and increase the binding affinity of AR-A to the androgen response element. Our results suggest that AR-A lacks the ability to stimulate cell proliferation possibly due to reduced binding of AR co-activating proteins to the truncated N-terminal transactivation domain rather than due to impaired stability of the AR-A isoform.
Steroids 01/2004; 68(14):1179-87. · 2.83 Impact Factor
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Bettina Felletschin,
Peter Bauer,
Uwe Walter,
Stephanie Behnke,
Jörg Spiegel,
Ilona Csoti, Ulrike Sommer,
Björn Zeiler,
Georg Becker,
Olaf Riess,
Daniela Berg
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ABSTRACT: Recently, an insertional mutation in the ferritin-L gene was reported in some patients with familial basal ganglia degeneration, which, however, could not be detected in another Parkinson's disease (PD) population. We investigated 186 PD patients, in whom an increased amount of iron of the substantia nigra (SN) was priorly identified by transcranial ultrasound, for mutations of the whole coding region of ferritin-L and ferritin-H by denaturing high-pressure liquid chromatography and subsequent sequencing. In the ferritin-L gene two silent mutations were detected. In the ferritin-H gene the sequence variation 161A-->G was found in one patient but none of the 186 controls. Although functional analysis will show, whether this sequence variation might be causative for single cases of PD, the results indicate that mutations in the ferritin genes are not a common cause for PD with increased levels of iron of the SN.
Neuroscience Letters 11/2003; 352(1):53-6. · 2.11 Impact Factor
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ABSTRACT: Adhesion of bone cells to the extracellular matrix is a crucial requirement for osteoblastic development and function. Adhesion receptors connect the extracellular matrix with the cyto-skeleton and convey matrix deformation into the cell. We tested the hypothesis that sex hormones modulate mechanoperception of human osteoblastic cells (HOB) by affecting expression of adhesion molecules like fibronectin and the fibronectin receptor. Only dihydrotestosterone (DHT), but not 17beta-estradiol, stimulated fibronectin (137%) and fibronectin receptor (252%) protein expression. The effects of deformation strain on HOB metabolism were investigated in a FlexerCell strain unit. Cyclically applied strain (2.5% elongation) increased DNA synthesis (125%) and interleukin-6 (IL-6) production (170%) without significantly affecting alkaline phosphatase (AP) activity, type I collagen (PICP), or osteoprotegerin (OPG) secretion. 10 nM DHT pretreatment abolished the mitogenic response of HOB to strain and increased AP activity (119%), PICP (163%), and OPG production (204%). In conclusion, mechanical strain stimulates bone remodeling by increasing HOB mitosis and IL-6 production. DHT enhances the osteoanabolic impact of deformation strain by increasing bone formation via increased AP activity and PICP production. At the same time, bone resorption is inhibited by decreased IL-6 and increased OPG secretion into the bone microenvironment.
Journal of Experimental Medicine 12/2002; 196(10):1387-92. · 13.85 Impact Factor
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ABSTRACT: This study compares plasma endothelin-1 (ET-1) levels in patients with diabetes mellitus or hypertension with healthy controls, and investigates whether ET-1 levels are correlated with glycemic control, metabolic parameters, and vascular complications.
The study population consisted of 103 patients with type 1 diabetes, 124 patients with type 2 diabetes, 35 hypertensive patients without diabetes mellitus, and 99 controls.
Plasma ET-1 concentrations were significantly higher in patients with type 1 diabetes (0.28 +/- 0.34 fmol/mL, P =.001), type 2 diabetes (0.31 +/- 0.32 fmol/mL, P <.0001), and hypertension (0.35 +/- 0.26 fmol/mL, P <.0001) compared to controls (0.08 +/- 0.13 fmol/mL). Diabetic patients taking angiotensin converting enzyme (ACE) inhibitors had significantly lower plasma ET-1 levels than patients without (0.22 +/- 0.20 fmol/mL v 0.38 +/- 0.39 fmol/mL, P =.029). There were significant associations between ET-1 levels and age (r = 0.38, P <.05) and systolic blood pressure (BP) (r = 0.27, P <.05) in healthy controls. In diabetes we found only nonsignificant associations between ET-1 levels and age or vascular complications and a weak association between plasma ET-1 levels and glycemic control.
Patients with diabetes or hypertension have elevated ET-1 levels, but do not exhibit positive correlations between ET-1 levels and BP, which was observed in healthy controls. Increased ET-1 levels do not induce hypertension in diabetes, but were lower in diabetic patients taking ACE inhibitors compared to those without ACE inhibitors. There is no significant association between ET-1 levels and vascular complications. These findings suggest that the plasma ET-1 level is not a marker of endothelial dysfunction but changes in plasma ET-1 levels may precede vascular complications associated with hypertension and diabetes.
American Journal of Hypertension 12/2002; 15(11):967-72. · 3.18 Impact Factor
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ABSTRACT: Adhesion of bone cells to the extracellular matrix is a crucial requirement for osteoblastic development and function. Adhesion
receptors connect the extracellular matrix with the cyto-skeleton and convey matrix deformation into the cell. We tested the
hypothesis that sex hormones modulate mechanoperception of human osteoblastic cells (HOB) by affecting expression of adhesion
molecules like fibronectin and the fibronectin receptor. Only dihydrotestosterone (DHT), but not 17β-estradiol, stimulated
fibronectin (137%) and fibronectin receptor (252%) protein expression. The effects of deformation strain on HOB metabolism
were investigated in a FlexerCell® strain unit. Cyclically applied strain (2.5% elongation) increased DNA synthesis (125%) and interleukin-6 (IL-6) production
(170%) without significantly affecting alkaline phosphatase (AP) activity, type I collagen (PICP), or osteoprotegerin (OPG)
secretion. 10 nM DHT pretreatment abolished the mitogenic response of HOB to strain and increased AP activity (119%), PICP
(163%), and OPG production (204%). In conclusion, mechanical strain stimulates bone remodeling by increasing HOB mitosis and
IL-6 production. DHT enhances the osteoanabolic impact of deformation strain by increasing bone formation via increased AP
activity and PICP production. At the same time, bone resorption is inhibited by decreased IL-6 and increased OPG secretion
into the bone microenvironment.
Journal of Experimental Medicine 11/2002; 196(10):1387-1392. · 13.85 Impact Factor
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ABSTRACT: PurposeOsteoprotegerin (OPG) affects bone metabolism by intercepting the RANK–RANKL interaction which prevents osteoclastic differentiation and consequently reduces bone resorption. Different bone phenotypes of mice overexpressing OPG and of mice with knockdown of receptor activator of NF-κB (RANK) or RANK-ligand (RANKL) suggest that the mechanism of action of the OPG–RANKL–RANK system in regulating bone remodeling is not completely understood. Furthermore, OPG increases bone mass and density independently from reduced osteoclastogenesis which is consistent with the possibility that OPG may directly affect bone metabolism beyond its known role as decoy receptor for RANKL.MethodsWe treated primary human osteoblastic cells with OPG and inhibitory anti-RANKL antibodies and measured cellular ALP activity, in vitro mineralization, vitronectin receptor protein expression and ERK phosphorylation. We also analyzed the mRNA co-expression of ALP and OPG ex vivo in bone biopsies from acute and old stable vertebral fractures.ResultsOPG directly increased ALP activity and in vitro mineralization of HOC, enhanced expression of the vitronectin receptor thereby increasing adherence of HOC to vitronectin and stimulated ERK phosphorylation. All OPG-mediated effects could be prevented by RANKL antibodies or RANKL–siRNA transfection and MAPK inhibitor PD98059 reduced the stimulatory effect of OPG on integrin αv expression. In acutely fractured vertebrae OPG and ALP mRNA expression was significantly increased compared to stable vertebral fractures. In conclusion, OPG exerts direct osteoanabolic effects on HOC metabolism via RANKL in addition to its well described role as decoy receptor for RANKL.
Biochemical and Biophysical Research Communications.
