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Skeletal Defects (skeletal + defect)
Selected AbstractsBapx1 homeobox gene gain-of-function mice show preaxial polydactyly and activated Shh signaling in the developing limbDEVELOPMENTAL DYNAMICS, Issue 9 2006Carla Tribioli Abstract To explore Bapx1 homeobox gene function in embryonic control of development, we employed a gain-of-function approach to complement our previous loss-of-function mutant analysis. We show that transgenic mice overexpressing Bapx1 are affected by skeletal defects including hindlimb preaxial polydactyly and tibial hypoplasia. Bapx1 overexpression generates limb anteroposterior patterning defects including induction of Shh signaling and ectopic activation of functions downstream of Shh signaling into the anterior region of the autopod. Moreover, Bapx1 overexpression stimulates formation of limb prechondrogenic condensations. We also show that Shh is reciprocally able to activate Bapx1 expression in mouse embryos as the orthologous hedgehog (hh) does with the bagpipe/Bapx1 gene in Drosophila. Our results indicate that Bapx1 can modulate appendicular skeletal formation, that the genetic hierarchy between Shh/hh and Bapx1/bagpipe has been conserved during evolution, and that in mouse embryos these two genes can influence one another in a genetically reciprocal manner. We conclude that it is reasonable to expect overexpression of Bapx1 in certain forms of polydactyly. Developmental Dynamics 235:2483,2492, 2006. © 2006 Wiley-Liss, Inc. [source] Truncation of the MLL gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryosGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 4 2001Paul Ayton Abstract Summary: The mixed lineage leukemia gene (MLL) was originally identified through its involvement in reciprocal translocations in leukemias. MLL codes for a large multidomain protein and bears homology to the Drosophila developmental control gene trithorax in two small domains in the amino terminal region, the central zinc finger domain and the carboxy SET domain. Like the Drosophila trx, MLL has also been shown to be a positive regulator of Hox gene expression. We have targeted Mll (the murine homologue of MLL) in exon 5 causing expression of three truncated in-frame Mll transcripts. These transcripts retain all or some of the AT hook motifs and the DMT domain. This mutant allele causes early in vivo preimplantation lethality of homozygous embryos prior to the 2-cell stage. Embryos cultured in vitro progress to the 2-cell stage, but further development is arrested. The heterozygotes exhibit mild skeletal defects as well as defects in some neuroectodermal derivatives. genesis 30:201,212, 2001. © 2001 Wiley-Liss, Inc. [source] Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1,HUMAN MUTATION, Issue 3 2009Frederick S. Kaplan Abstract Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development. Hum Mutat 0, 1,12, 2008. © 2008 Wiley-Liss, Inc. [source] Lack of teratogenicity of microcystin-LR in the mouse and toadJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2002N. Chernoff Abstract Microcystin-LR (MC-LR) is a cyanobacterial toxin generated by the organism Microcystis aeruginosa. Although the hepatotoxicity of this chemical has been characterized, the potential developmental toxicity in vertebrates has not been well studied. The purpose of this study was to elucidate the effects of this toxin on the in vivo and in vitro development of mammals and the development of an Anuran (toad). Initial acute toxicity experiments with female CD-1 mice were accomplished with MC-LR administered i.p. in saline. Lethality occurred at 128 and 160 µg kg ,1 and histopathology revealed massive hepatic necrosis with diffuse hemorrhage. Developmental toxicity studies were done with MC-LR administered i.p. for 2-day periods: gestation days 7,8, 9,10 or 11,12. Doses used ranged from 2 to 128 µg kg,1. On gestation day 17, fetuses were weighed and analyzed for gross morphological and skeletal defects. No treatment-related differences were seen in litter size, viability, weight or the incidence of anomalies. Groups of dams dosed with 32,128 µg kg,1 on gestation days 7,8, 9,10 or 11,12 were allowed to give birth and the growth and development of their pups were followed postnatally. There were no significant effects noted in the offspring of the treated dams. Neurulation-staged CD-1 mouse conceptuses were exposed to 50,1000 nM MC-LR in whole embryo culture for 24 h. No significant increase in abnormalities or developmental delays was observed. Finally, exposure of the developing toad. Bufo arenarum was done from stage 17 (tail bud) for 10 days at concentrations of 1,20 mg l,1. No effect on morphological development or survival was noted in any exposed groups. These data indicate that microcystin does not appear to affect development adversely in the mouse (in vivo or in vitro) or the toad at the doses and exposure parameters used. Copyright © 2002 John Wiley & Sons, Ltd. [source] Repair of segmental defects in rabbit humeri with titanium fiber mesh cylinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymerJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 2 2002Narumichi Murakami Abstract To develop a new technology that enhances the regeneration potential of bone and the repair of large intercalated defects in long bone, recombinant human bone morphogenetic protein-2 (BMP-2; 20 ,g or 40 ,g) was mixed in a polymer gel (poly-lactic acid-polyethyleneglycol block copolymer; PLA-PEG; 200 mg) and incorporated into titanium fiber-mesh cylinders. Three 5-mm cylinders were placed end-to-end to fill a 15-mm defect created in the humeri of adult rabbits and were stabilized by an intramedullary rod. In controls, the titanium fiber-mesh cylinders were combined with PLA-PEG in the absence of BMP. Six weeks after implantation, new bone had formed on the surface of the implant and had bridged the defect. All of the defects (5/5) treated by cylinders containing 120 ,g (40 ,g × 3) of BMP were repaired completely. New bone formation was also found inside the pores of the cylinders. The defect was not repaired in the control animals. These results demonstrate that these new composite implants fabricated by combining rhBMP, synthetic degradable polymers and compatible biomaterials enhance the regeneration potential of bone. Thus, it is possible that large skeletal defects can be repaired using this prosthesis in lieu of autogenous bone graft. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 169,174, 2002 [source] Targeted Expression of SHH Affects Chondrocyte Differentiation, Growth Plate Organization, and Sox9 Expression,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2004Sara Tavella Abstract The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis with major alterations in long bones because of defects in chondrocyte differentiation. Introduction: Hedgehogs (Hhs) are a family of secreted polypeptides that play important roles in vertebrate development, controlling many critical steps of cell differentiation and patterning. Skeletal development is affected in many different ways by Hhs. Genetic defects and anomalies of Hhs signaling pathways cause severe abnormalities in the appendicular, axial, and cranial skeleton in man and other vertebrates. Materials and Methods: Genetic manipulation of mouse embryos was used to study in vivo the function of SHH in skeletal development. By DNA microinjection into pronuclei of fertilized oocytes, we have generated transgenic mice that express SHH specifically in chondrocytes using the cartilage-specific collagen II promoter/enhancer. Transgenic skeletal development was studied at different embryonic stages by histology. The expression pattern of specific chondrocyte molecules was studied by immunohistochemistry and in situ hybridization. Results: Transgenic mice died at birth with severe craniorachischisis and other skeletal defects in ribs, sternum, and long bones. Detailed analysis of long bones showed that chondrocyte differentiation was blocked at prehypertrophic stages, hindering endochondral ossification and trabecular bone formation, with specific defects in different limb segments. The growth plate was highly disorganized in the tibia and was completely absent in the femur and humerus, leading to skeletal elements entirely made of cartilage surrounded by a thin layer of bone. In this cartilage, chondrocytes maintained a columnar organization that was perpendicular to the bone longitudinal axis and directed toward its outer surface. The expression of SHH receptor, Patched-1 (Ptc1), was greatly increased in all cartilage, as well as the expression of parathyroid hormone-related protein (PTHrP) at the articular surface; while the expression of Indian Hedgehog (Ihh), another member of Hh family that controls the rate of chondrocyte maturation, was greatly reduced and restricted to the displaced chondrocyte columns. Transgenic mice also revealed the ability of SHH to upregulate the expression of Sox9, a major transcription factor implicated in chondrocyte-specific gene expression, in vivo and in vitro, acting through the proximal 6.8-kb-long Sox9 promoter. Conclusion: Transgenic mice show that continuous expression of SHH in chondrocytes interferes with cell differentiation and growth plate organization and induces high levels and diffuse expression of Sox9 in cartilaginous bones. [source] Qualitative disorders of platelets and megakaryocytesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2005A. T. NURDEN Summary., Qualitative disorders of platelet function and production form a large group of rare diseases which cover a multitude of genetic defects that by and large have as a common symptom, excessive mucocutaneous bleeding. Glanzmann thrombasthenia, is enabling us to learn much about the pathophysiology of integrins and of how ,IIb,3 functions. Bernard,Soulier syndrome, an example of macrothrombocytopenia, combines the production of large platelets with a deficit or non-functioning of the major adhesion receptor of platelets, the GPIb-IX-V complex. Amino acid substitutions in GPIb,, may lead to up-regulation and spontaneous binding of von Willebrand factor as in Platelet-type von Willebrand disease. In disorders with defects in the MYH9 gene, macrothrombocytopenias are linked to modifications in kidney, eye or ear, whereas other inherited thrombocytopenias variously link a low platelet count with a propensity to leukemia, skeletal defects, learning impairment, and abnormal red cells. Defects of secretion from platelets include an abnormal , -granule formation as in the gray platelet syndrome (with marrow myelofibrosis), and of organelle biogenesis in the Hermansky,Pudlak and Chediak,Higashi syndromes where platelet dense body defects are linked to abnormalities of other lysosomal-like organelles including melanosomes. Finally, defects involving surface receptors (P2Y12, TP,) for activating stimuli, of proteins essential for signaling pathways (including Wiskott,Aldrich syndrome), and of platelet-derived procoagulant activity (Scott syndrome) show how studies on platelet disorders are helping unravel the pathways of primary hemostasis. [source] Reconstruction of large posttraumatic skeletal defects of the forearm by vascularized free fibular graft,MICROSURGERY, Issue 6 2004Roberto Adani M.D. Vascularized bone graft is most commonly applied for reconstruction of the lower extremity; indications for its use in the reconstruction of the upper extremity have expanded in recent years. Between 1993,2000, 12 patients with segmental bone defects following forearm trauma were managed with vascularized fibular grafts: 6 males and 6 females, aged 39 years on average (range, 16,65 years). The reconstructed site was the radius in 8 patients and the ulna in 4. The length of bone defect ranged from 6,13 cm. In 4 cases, the fibular graft was harvested and used as a vascularized fibula osteoseptocutaneous flap. To achieve fixation of the grafted fibula, plates were used in 10 cases, and screws and Kirschner wires in 2. In the latter 2 cases, an external skeletal fixator was applied to ensure immobilization of the extremity. The follow-up period ranged from 10,93 months. Eleven grafts were successful. The mean period to obtain radiographic bone union was 4.8 months (range, 2.5,8 months). Fibular grafts allow the use of a segment of diaphyseal bone which is structurally similar to the radius and ulna and of sufficient length to reconstruct most skeletal defects of the forearm. The vascularized fibular graft is indicated in patients with intractable nonunions where conventional bone grafting has failed or large bone defects, exceeding 6 cm, are observed in the radius or ulna. © 2004 Wiley-Liss, Inc. Microsurgery 24:423,429, 2004. [source] Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctataPRENATAL DIAGNOSIS, Issue 9 2003N. V. Whittock Abstract X-linked dominant chondrodysplasia punctata, (CDPX2,MIM302960) also known as Conradi,Hünermann,Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2. Copyright © 2003 John Wiley & Sons, Ltd. [source] Osteogenic Induction of Adipose-derived Stromal Cells: Not a Requirement for Bone Formation In VivoARTIFICIAL ORGANS, Issue 1 2010Xiaoyu Li Abstract Osteogenic induction was regarded as an indispensable step for adipose-derived stromal cells (ADSCs) to have osteogenic ability. Non-induced ADSCs can also produce bone in vivo and heal skeletal defects. The present study aimed to compare the bone-forming ability of osteogenically induced ADSCs and non-induced ADSCs in vivo. Tissue-engineered constructs were prepared from osteogenically induced or non-induced ADSCs and porous hydroxyapatite/beta-tricalcium phosphate scaffolds. A scaffold without cells and an empty defect group were used as control. All were implanted in rat critical calvarial defects. After implantation for 6 and 12 weeks, bone formation was analyzed using histomorphometry and microcomputed tomography; there were no significant differences in the formation of new bone between osteogenically induced ADSCs and non-induced ADSCs (P > 0.05). In conclusion, osteogenic induction of ADSCs is not an indispensable step for bone formation in vivo. Non-induced ADSCs can also be used as seeding cells to construct bone tissue. [source] Interactive effects of cadmium and all- trans -retinoic acid on the induction of forelimb ectrodactyly in C57BL/6 mice,BIRTH DEFECTS RESEARCH, Issue 1 2006Grace S. Lee Abstract BACKGROUND Most toxicological studies have tested single chemical agents at relatively high doses, and fewer studies have addressed the toxic effects of chemical interactions. It is important to understand the toxicity of chemical mixtures in order to assess the more realistic risks of environmental and occupational exposures. A number of chemicals are known to induce a predominantly postaxial forelimb ectrodactyly in C57BL/6 mice, including acetazolamide, ethanol, cadmium, valproic acid, carbon dioxide, dimethadione, phenytoin, and 13- cis -retinoic acid and all- trans -retinoic acid (RA). In the present study, the interactive effects of coadministration of cadmium and RA on developing limbs were investigated. METHODS Pregnant C57BL/6 mice were treated with different intraperitoneal (IP) doses of cadmium chloride (CdCl2) and/or RA on gestational day (GD) 9.5, and fetuses were collected on GD 18 and double stained for examination of skeletal defects. RESULTS When RA was given simultaneously with cadmium, a significant increase in the incidence and severity of forelimb ectrodactyly (predominantly postaxial) was observed compared to the results with corresponding doses of cadmium or RA alone. When mice were exposed to subthreshold doses of both cadmium (0.5 mg/kg) and RA (1 mg/kg), the combined treatment exceeded the threshold, resulting in forelimb ectrodactyly in 19% of the fetuses. Moreover, coadministration of cadmium and RA at doses exceeding the respective thresholds showed a synergistic effect, that is, 92% of fetuses were found with the forelimb defect as opposed to 10% if the response were additive. CONCLUSIONS The findings demonstrate that concurrent exposure to these teratogens can have a synergistic effect and that subteratogenic doses may combine to exceed a threshold. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc. [source] Carbon monoxide-induced axial skeletal dysmorphogenesis in the chick embryo,,BIRTH DEFECTS RESEARCH, Issue 4 2003Peter G. Alexander Abstract BACKGROUND Congenital axial skeletal defects affect two to three individuals per 1,000 live births. Without strong evidence for heritability, the cause is assumed to be multi-factorial. Carbon monoxide (CO), an increasingly prevalent environmental toxicant, is a potential environmental component in the etiology of these defects. The chick embryo is a useful model for the characterization and assessment of the mechanism(s) of action of basic developmental mechanisms. METHODS We have determined a critical period and dose for CO teratogenicity and established a model of CO-induced axial skeletal dysmorphogenesis in the chick embryo. The resulting phenotypes reveal a spectrum of axial skeletal defects ranging from minor defects of the vertebral canal and inter,vertebral discs, to thoraco,lumbar scoliosis, to a tailless phenotype reminiscent of caudal dysgenesis syndrome. These axial skeletal defects have been related to earlier developmental defects in somitogenesis, including errors in segmentation and epithelialization and the expression of the somitic epithelialization factor, Paraxis. We have examined patterns of cell death and apoptosis in CO exposed chick embryos to assess the target tissue(s) involved in the teratogenicity of CO. RESULTS With respect to the embryonic axis, the neural tube was found to be the most sensitive to CO-induced apoptosis, followed by the somitic mesoderm and Hensen's node. CONCLUSIONS We hypothesize that the somitic defects and the resulting axial skeletal dysmorphogenesis are caused by disrupted neural tube or ectoderm functions related to somite formation and maintenance. We also hypothesize that CO-induced dysmorphogenesis at this critical period of somitogenesis is caused by the overabundance of CO acting endogenously as a cellular signal, while coincidentally exerting its influence as a toxicant of oxygen delivery or utilization. Birth Defects Research (Part A) 67:219,230, 2003. Published 2003 Wiley-Liss, Inc. [source] | |||||||||||||