Distribution of genes for parathyroid hormone (PTH)—related peptide, Indian hedgehog, PTH receptor and patched in the process of experimental spondylosis in mice

2002 ◽  
Vol 97 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Takanobu Nakase ◽  
Kenta Ariga ◽  
Wenxiang Meng ◽  
Motoki Iwasaki ◽  
Tetsuya Tomita ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Indian Hedgehog ◽  
Molecular Signaling ◽  
Content Type ◽  
Chondrocyte Maturation ◽  
Related Peptide ◽  
Fine Print

Object. Little is known about the molecular mechanisms underlying the process of spondylosis. The authors determined the extent of genetic localization of major regulators of chondrogenesis such as Indian hedgehog (Ihh) and parathyroid hormone (PTH)—related peptide (PTHrP) and their receptors during the development of spondylosis in their previously established experimental mouse model. Methods. Experimental spondylosis was induced in 5-week-old ICR mice. The cervical spines were chronologically harvested, and histological sections were prepared. Messenger (m) RNA for PTHrP, Ihh, PTH receptor (PTHR; a receptor for PTHrP), patched (Ptc; a receptor for Ihh), bone morphogenetic protein (BMP)—6, and collagen type X (COL10; a marker for mature chondrocyte) was localized in the tissue sections by performing in situ hybridization. In the early stage, mRNA for COL10, Ihh, and BMP-6 was absent; however, mRNA for PTHrP, PTHR, and Ptc was detected in the anterior margin of the cervical discs. In the late stage, evidence of COL10 mRNA began to be detected, and transcripts for Ihh, PTHrP, and BMP-6 were localized in hypertrophic chondrocytes adjacent to the bone-forming area in osteophyte. Messenger RNA for Ptc and PTHR continued to localize at this stage. In control mice, expression of these genes was absent. Conclusions. The localization of PTHrP, Ihh, BMP-6, and the receptors PTHR and Ptc demonstrated in the present experimental model indicates the possible involvement of molecular signaling by PTHrP (through the PTHR), Ihh (through the Ptc), and BMP-6 in the regulation of chondrocyte maturation leading to endochondral ossification in spondylosis.

Distribution of genes for bone morphogenetic protein—4, —6, growth differentiation factor—5, and bone morphogenetic protein receptors in the process of experimental spondylosis in mice

2001 ◽  
Vol 94 (1) ◽  
pp. 68-75 ◽  
Author(s):  
Takano Bunakase ◽  
Kenta Ariga ◽  
Shimpei Miyamoto ◽  
Shin'ya Okuda ◽  
Tetsuya Tomita ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Mice Model ◽  
Content Type ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Fine Print ◽  
In Cells

Object. Because little is known about the molecular mechanisms underlying the process of spondylosis, the authors examined the extent of genetic localization of several members of bone morphogenetic protein (BMP) and BMP receptors in chondrogenesis during the process of inducing spondylosis in their previously established experimental mice model. Methods. Experimental spondylosis was induced in 5-week-old ICR mice. The cervical spine was harvested chronologically, and histological sections were prepared. Messenger RNA for BMP-4, growth and differentiation (GDF)—5, BMP-6, and BMP receptors (ALK-3, -6, and BMP-RII) was localized in the tissue sections by in situ hybridization. In the early stage, BMP-4—derived mRNA was localized mainly in cells in the anterior margin of the cervical discs, together with ALK-6 and BMP-RII mRNA. No GDF-5 and BMP-6 mRNA was detected at this stage. In the late stage, cells positive for BMP-4 decreased, whereas GDF-5 and BMP-6 mRNA were localized in cells undergoing chondrogenesis. The ALK-3 mRNA began to appear in this stage, as did ALK-6 and BMP-RII. Conclusions. The localization of transcripts for BMP-4, -6, and GDF-5 as well as BMP receptors shown during the present experimental model indicate the possible involvement of molecular signaling by these BMPs in the chondrogenic progress in spondylosis.

scholarly journals Bcl-2 Lies Downstream of Parathyroid Hormone–related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development

1997 ◽  
Vol 136 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Michael Amling ◽  
Lynn Neff ◽  
Sakae Tanaka ◽  
Daisuke Inoue ◽  
Keisuke Kuida ◽  
...  
Keyword(s):  
Cell Death ◽  
Parathyroid Hormone ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Skeletal Development ◽  
Skeletal Maturation ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Maturation ◽  
Related Peptide ◽  
Parathyroid Hormone Related Peptide

Parathyroid hormone–related peptide (PTHrP) appears to play a major role in skeletal development. Targeted disruption of the PTHrP gene in mice causes skeletal dysplasia with accelerated chondrocyte maturation (Amizuka, N., H. Warshawsky, J.E. Henderson, D. Goltzman, and A.C. Karaplis. 1994. J. Cell Biol. 126:1611–1623; Karaplis, A.C., A. Luz, J. Glowacki, R.T. Bronson, V.L.J. Tybulewicz, H.M. Kronenberg, and R.C. Mulligan. 1994. Genes Dev. 8: 277–289). A constitutively active mutant PTH/PTHrP receptor has been found in Jansen-type human metaphyseal chondrodysplasia, a disease characterized by delayed skeletal maturation (Schipani, E., K. Kruse, and H. Jüppner. 1995. Science (Wash. DC). 268:98– 100). The molecular mechanisms by which PTHrP affects this developmental program remain, however, poorly understood. We report here that PTHrP increases the expression of Bcl-2, a protein that controls programmed cell death in several cell types, in growth plate chondrocytes both in vitro and in vivo, leading to delays in their maturation towards hypertrophy and apoptotic cell death. Consequently, overexpression of PTHrP under the control of the collagen II promoter in transgenic mice resulted in marked delays in skeletal development. As anticipated from these results, deletion of the gene encoding Bcl-2 leads to accelerated maturation of chondrocytes and shortening of long bones. Thus, Bcl-2 lies downstream of PTHrP in a pathway that controls chondrocyte maturation and skeletal development.

Posttreatment with adenovirus-mediated gene transfer of calcitonin gene—related peptide to reverse cerebral vasospasm in dogs

2002 ◽  
Vol 97 (1) ◽  
pp. 136-142 ◽  
Author(s):  
Motoyoshi Satoh ◽  
Eddie Perkins ◽  
Hitoshi Kimura ◽  
Jiping Tang ◽  
Yi Chun ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cerebral Vasospasm ◽  
Treated Group ◽  
Positive Staining ◽  
Cmv Promoter ◽  
Content Type ◽  
Related Peptide ◽  
Arterial Blood ◽  
Blood Injection ◽  
Fine Print

Object. Gene transfer to cerebral vessels is a promising new therapeutic approach for cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was undertaken to explore whether a delayed treatment with adenovirus encoding the prepro-calcitonin gene—related peptide (CGRP), 2 days after initial blood injection, reduces cerebral vasospasm in a double-hemorrhage model of severe vasospasm in dogs. Methods. In 20 dogs, arterial blood was injected into the cisterna magna on Days 0 and 2. Thirty minutes after the second blood injection, the animals received either adenovirus encoding the prepro-CGRP gene (AdCMVCGRP—treated group, eight dogs) or adenovirus encoding the β-galactosidase gene (AdCMVβgal—treated group, six dogs) under the cytomegalovirus (CMV) promoter. One group of dogs did not receive treatment and served as controls (control SAH group, six dogs). Angiography was performed on Days 0 and 7 to assess cerebral vasospasm. On Day 7 following angiography, the animals were killed and their brains were stained with X-gal to detect the distribution of gene expression. Cerebrospinal fluid (CSF) was also tested for CGRP immunoreactivity. Severe vasospasm was observed in control SAH dogs on Day 7, and the mean basilar artery (BA) diameter was 53.4 ± 5.5% of the value measured on Day 0. Treatment with AdCMVβgal did not alter vasospasm (the BA diameter was 55 ± 3.9% of that measured on Day 0). The leptomeninges and adventitia of the BAs of dogs treated using AdCMVβgal demonstrated positive staining with X-gal. High levels of CGRP were measured in CSF from dogs that received AdCMVCGRP. In the group treated with AdCMVCGRP, vasospasm was significantly reduced (the BA diameter was 78.2 ± 5.3% of that measured on Day 0, p < 0.05 compared with the control SAH group and the AdCMVβgal group). Conclusions. In a model of severe vasospasm in dogs, gene transfer of CGRP after injection of blood attenuated cerebral vasospasm after SAH.

Calpain-calpastatin system of canine basilar artery in vasospasm

1993 ◽  
Vol 79 (4) ◽  
pp. 537-543 ◽  
Author(s):  
Ikuya Yamaura ◽  
Eiichi Tani ◽  
Takaomi C. Saido ◽  
Koichi Suzuki ◽  
Nobutaka Minami ◽  
...  
Keyword(s):  
Basilar Artery ◽  
Early Stage ◽  
Local Application ◽  
Neutral Protease ◽  
Control Group ◽  
Calpain Activity ◽  
Fresh Blood ◽  
Content Type ◽  
Canine Basilar Artery ◽  
Fine Print

✓ Vasospasm was produced in the canine basilar artery by a two-hemorrhage method, while contraction was induced in the normal canine basilar artery by a local application of KCl or serotonin after transclival exposure. The control animals were injected with saline instead of fresh blood. The activation of μ-calpain, a Ca++-dependent neutral protease, in the basilar artery was studied by evaluating the conversion from its inactivated into its activated form on immunoblots. In addition, the activity of calpastatin, an intrinsic inhibitor of calpain, in the basilar artery was determined by assay. The majority of the μ-calpain was inactivated in the control group. In the spastic group, μ-calpain was generally activated markedly in the early stage of vasospasm and moderately thereafter. The contraction induced by KCl or serotonin application was classified into the early phasic and the later tonic stages; μ-calpain was usually activated in the phasic stage and inactivated in the tonic stage. Calpastatin activity was significantly decreased during vasospasm, whereas it was not significantly changed in KCl- or serotonin-induced contraction. The final activity of μ-calpain results from the balance of μ-calpain and calpastatin. This suggests that μ-calpain activity was enhanced continuously in the spastic group and transiently in the KCl or serotonin group, and that the continuous activation of μ-calpain during vasospasm probably induced more proteolytic changes compared to those in the KCl or serotonin group.

Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist

1999 ◽  
Vol 91 (1) ◽  
pp. 93-99 ◽  
Author(s):  
Keith E. Friend ◽  
Robert Radinsky ◽  
Ian E. McCutcheon
Keyword(s):  
Growth Hormone ◽  
Growth Rate ◽  
Receptor Antagonist ◽  
Messenger Rna ◽  
Thymidine Incorporation ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Content Type ◽  
Gh Receptor ◽  
Fine Print

Object. This study was undertaken to explore the effects of growth hormone (GH) and the GH-stimulated peptide insulin-like growth factor—1 (IGF-1) on the growth rate of meningiomas.Methods. Polymerase chain reaction and ribonuclease protection assays were used to demonstrate that GH receptor messenger RNA was present in all 14 meningioma specimens studied, regardless of tumor grade. Both wild type (GHRwt) and a previously described exon 3 deletion isoform (GHRd3) of the GH receptor were identified in individual tumor specimens. The importance of the GH receptor was assessed using a GH receptor antagonist (B2036). Blockade of the GH receptor with B2036 reduced serum-induced DNA synthesis, as measured by thymidine incorporation, by 8 to 33% (mean 20%) in primary meningioma cultures. Tumors that expressed the GHRwt and GHRd3 isoforms, or a combination of the two, were all responsive to antagonist treatment. The importance of IGF-1 in stimulating meningioma cell growth was also assessed. It was found that IGF-1 increased thymidine incorporation in primary meningioma cultures in a dose-dependent manner: 1 ng/ml, 5 ng/ml, and 10 ng/ml resulted in increases in thymidine incorporation of 21%, 43%, and 176%, respectively, over baseline values.Conclusions. In these studies the authors demonstrate that activation of the GH/IGF-1 axis significantly increases the growth rate of meningiomas. Blockade of the GH receptor on tumor cells inhibited tumor growth. If these findings are confirmed in animal studies, agents that downregulate the GH/IGF-1 axis might represent a potential adjuvant therapy in the management of patients with meningioma.

Intraoperative magnetic resonance imaging during transsphenoidal surgery

2001 ◽  
Vol 95 (3) ◽  
pp. 381-390 ◽  
Author(s):  
Rudolf Fahlbusch ◽  
Oliver Ganslandt ◽  
Michael Buchfelder ◽  
Werner Schott ◽  
Christopher Nimsky
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Early Stage ◽  
Intraoperative Imaging ◽  
Tumor Resection ◽  
Tumor Removal ◽  
Content Type ◽  
Early Evaluation ◽  
Flexible Coil ◽  
Fine Print

Object. The aim of this study was to evaluate whether intraoperative magnetic resonance (MR) imaging can increase the efficacy of transsphenoidal microsurgery, primarily in non—hormone-secreting intra- and suprasellar pituitary macroadenomas. Methods. Intraoperative imaging was performed using a 0.2-tesla MR imager, which was located in a specially designed operating room. The patient was placed supine on the sliding table of the MR imager, with the head placed near the 5-gauss line. A standard flexible coil was placed around the patient's forehead. Microsurgery was performed using MR-compatible instruments. Image acquisition was started after the sliding table had been moved into the center of the magnet. Coronal and sagittal T1-weighted images each required over 8 minutes to acquire, and T2-weighted images were obtained optionally. To assess the reliability of intraoperative evaluation of tumor resection, the intraoperative findings were compared with those on conventional postoperative 1.5-tesla MR images, which were obtained 2 to 3 months after surgery. Among 44 patients with large intra- and suprasellar pituitary adenomas that were mainly hormonally inactive, intraoperative MR imaging allowed an ultra-early evaluation of tumor resection in 73% of cases; such an evaluation is normally only possible 2 to 3 months after surgery. A second intraoperative examination of 24 patients for suspected tumor remnants led to additional resection in 15 patients (34%). Conclusions. Intraoperative MR imaging undoubtedly offers the option of a second look within the same surgical procedure, if incomplete tumor resection is suspected. Thus, the rate of procedures during which complete tumor removal is achieved can be improved. Furthermore, additional treatments for those patients in whom tumor removal was incomplete can be planned at an early stage, namely just after surgery.

Comparative genomic hybridization analysis of craniopharyngiomas

2003 ◽  
Vol 98 (1) ◽  
pp. 162-164 ◽  
Author(s):  
Shlomit Rienstein ◽  
Eric F. Adams ◽  
David Pilzer ◽  
Ayala Aviram Goldring ◽  
Boleslaw Goldman ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Genomic Alteration ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Dna Copy Number ◽  
Content Type ◽  
Fine Print

Object. Craniopharyngioma is the most common childhood brain tumor and is thought to arise from embryonic remnants of the Rathke pouch. Some craniopharyngiomas are monoclonal in origin and hence presumably harbor somatic genetic alterations, although the precise molecular mechanisms involved in craniopharyngioma development are unknown. The goal of this study was to identify genetic alterations in craniopharyngiomas. Methods. To gain insight into the molecular mechanisms involved in development of these tumors, the authors analyzed nine adamantinomatous craniopharyngiomas by using comparative genomic hybridization. Six tumors (67%) displayed at least one genomic alteration, and three had six or more alterations. Only two tumors displayed a decrease in DNA copy number, and in all others an increase in DNA copy number was noted. Conclusions. The authors conclude that a subset of craniopharyngiomas consists of monoclonal tumors arising from activation of oncogenes located at specific chromosomal loci.

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