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The nature and biology of basement membranes.
Pozzi A, Yurchenco PD, Iozzo RV
(2017) Matrix Biol 57-58: 1-11
MeSH Terms: Agrin, Animals, Basement Membrane, Bone Diseases, Developmental, Collagen Type IV, Diabetic Nephropathies, Extracellular Matrix, Gene Expression Regulation, Heparan Sulfate Proteoglycans, Humans, Laminin, Lupus Nephritis, Mechanotransduction, Cellular, Membrane Glycoproteins, Mutation, Protein Isoforms
Show Abstract · Added March 26, 2017
Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as passive scaffolds segregating polarized cells, such as epithelial or endothelial cells, from the underlying mesenchyme, basement membranes have now reached the center stage of biology. They play a multitude of roles from blood filtration to muscle homeostasis, from storing growth factors and cytokines to controlling angiogenesis and tumor growth, from maintaining skin integrity and neuromuscular structure to affecting adipogenesis and fibrosis. Here, we will address developmental, structural and biochemical aspects of basement membranes and discuss some of the pathogenetic mechanisms causing diseases linked to abnormal basement membranes.
Copyright © 2017 Elsevier B.V. All rights reserved.
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16 MeSH Terms
A newborn with severe skeletal dysplasia.
Maalouf FI, Coggins SA, Phillips JA, Stefanescu BM, Weitkamp JH
(2016) Arch Dis Child Educ Pract Ed 101: 147
MeSH Terms: Bone Diseases, Developmental, Calcification, Physiologic, Extremities, Humans, Infant, Newborn, Male, Skull, Thorax, Treatment Outcome
Added October 16, 2015
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9 MeSH Terms
Prevalence of Hypertension in Pediatric Tibia Vara and Slipped Capital Femoral Epiphysis.
Taussig MD, Powell KP, Cole HA, Nwosu SK, Hunley T, Romine SE, Iwinski H, Talwalkar V, Warhoover T, Lovejoy SA, Mencio GA, Martus JE, Walker J, Milbrandt T, Schoenecker JG
(2016) J Pediatr Orthop 36: 877-883
MeSH Terms: Adolescent, Blood Pressure, Bone Diseases, Developmental, Child, Child, Preschool, Female, Humans, Hypertension, Male, Osteochondrosis, Prevalence, Risk Factors, Slipped Capital Femoral Epiphyses, United States
Show Abstract · Added February 22, 2016
BACKGROUND - Slipped capital femoral epiphysis (SCFE) and tibia vara (Blount disease) are associated with childhood obesity. However, the majority of obese children do not develop SCFE or tibia vara. Therefore, it is hypothesized that other obesity-related biological changes to the physis, in addition to increased biomechanical stress, potentiate the occurrence of SCFE and tibia vara. Considering that hypertension can impose pathologic changes in the physis similar to those observed in these obesity-related diseases we set out to determine the prevalence of hypertension in patients with SCFE and tibia vara.
METHODS - Blood pressure measurements were obtained in 44 patients with tibia vara and 127 patients with SCFE. Body mass index and blood pressure were adjusted for age, sex, and height percentiles utilizing normative distribution data from the CDC. These cohorts were compared with age-matched and sex-matched cohorts derived from an obesity clinic who did not have either bone disease. A multivariable proportional odds model was used to determine association.
RESULTS - The prevalence of prehypertension/hypertension was significantly higher in the tibia vara (64%) and SCFE cohort (64%) compared with respective controls (43%). Patients diagnosed with either SCFE or tibia vara had 2.5-fold higher odds of having high blood pressure compared with age-matched and sex-matched obese patients without bone disease. Sex, age, and race did not have a significant effect on a patient's blood pressure.
CONCLUSIONS - This is the first study to establish that the obesity-related bone diseases, SCFE and tibia vara, are significantly associated with high blood pressure. These data have immediate clinical impact as they demonstrate that children with obesity-related developmental bone disease have increased prevalence of undiagnosed and untreated hypertension. Furthermore, this prevalence study supports the hypothesis that hypertension in conjunction with increased biomechanical forces together potentiate the occurrence of SCFE and tibia vara. If proven true, it is plausible that hypertension may represent a modifiable risk factor for obesity-related bone disease.
LEVEL OF EVIDENCE - Level III-case-control study.
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14 MeSH Terms
Hemiepiphysiodesis Implants for Late-onset Tibia Vara: A Comparison of Cost, Surgical Success, and Implant Failure.
Funk SS, Mignemi ME, Schoenecker JG, Lovejoy SA, Mencio GA, Martus JE
(2016) J Pediatr Orthop 36: 29-35
MeSH Terms: Adolescent, Bone Diseases, Developmental, Child, Costs and Cost Analysis, Female, Hospital Costs, Humans, Male, Orthopedic Procedures, Osteochondrosis, Prosthesis Design, Prosthesis Failure, Retrospective Studies, Tibia, Treatment Outcome
Show Abstract · Added February 22, 2016
BACKGROUND - The purpose of this study was to compare hemiepiphysiodesis implants for late-onset tibia vara and to evaluate patient characteristics that may predict surgical failure.
METHODS - This is a retrospective review of late-onset tibia vara patients treated with temporary hemiepiphysiodesis from 1998 to 2012. Mechanical axis deviation (MAD), mechanical axis angle, mechanical lateral distal femoral angle, and medial proximal tibial angle were measured on standing bone length radiographs. Surgical failure was defined as residual deformity requiring osteotomy, revision surgery, or MAD exceeding 40 mm at the time of final follow-up. Implant failure was recorded. Costs included implants and disposables required for construct placement. Staple constructs included 2 or 3 staples. Plate constructs included the plate, screws, guide wires, and drill bits.
RESULTS - A total of 25 patients with 38 temporary lateral proximal tibia hemiepiphysiodeses met the inclusion criteria. The average body mass index (BMI) was 39.1 kg/m with an average follow-up of 3.0 years (minimum 1 y). Surgical failure occurred in 57.9% of patients. Greater BMI (P=0.05) and more severe deformity (MAD, mechanical axis angle, and medial proximal tibial angle; P<0.01) predicted higher rates of surgical failure. Younger age predicted higher rates of implant failure (P<0.01). There were no differences in surgical or implant failure between staple and plate systems. Hospital costs of plate constructs ($781 to $1244) were 1.5 to 3.5 times greater than the staple constructs ($332 to $498).
CONCLUSIONS - Greater BMI, more severe deformity, and younger age were predictive of surgical or implant failure. There was no difference in success between implant types, whereas the cost of plate constructs was 1.5 to 3.5 times greater than staples. The rate of surgical failure was high (58%) and consideration should be given to reserving hemiepiphysiodesis for patients with lower BMI and less severe deformity. In our population, if hemiepiphysiodesis was not offered to patients with BMI>35 or MAD>80 mm varus, the surgical failure rate would diminish to 28%. The failure rate outside these parameters would be 88%.
LEVEL OF EVIDENCE - Level II—Prognostic.
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15 MeSH Terms
Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1.
de la Croix Ndong J, Makowski AJ, Uppuganti S, Vignaux G, Ono K, Perrien DS, Joubert S, Baglio SR, Granchi D, Stevenson DA, Rios JJ, Nyman JS, Elefteriou F
(2014) Nat Med 20: 904-10
MeSH Terms: Adolescent, Alkaline Phosphatase, Animals, Bone Development, Bone Diseases, Developmental, Bone Morphogenetic Protein 2, Calcification, Physiologic, Cells, Cultured, Child, Child, Preschool, Collagen Type I, Collagen Type II, Diphosphates, Disease Models, Animal, Durapatite, Humans, Immunoglobulin G, Infant, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases, Neurofibromatosis 1, Neurofibromin 1, Osteoblasts, Osteogenesis, Phosphate Transport Proteins, Phosphoric Diester Hydrolases, Pyrophosphatases, Recombinant Fusion Proteins, Sp7 Transcription Factor, Transcription Factors
Show Abstract · Added July 28, 2014
Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.
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32 MeSH Terms
Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I.
Wang W, Nyman JS, Ono K, Stevenson DA, Yang X, Elefteriou F
(2011) Hum Mol Genet 20: 3910-24
MeSH Terms: Animals, Bone Diseases, Developmental, Bone Remodeling, Bone and Bones, Chondrocytes, Collagen Type II, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Female, Intervertebral Disc, Lovastatin, Mice, Mice, Knockout, Neurofibromatosis 1, Neurofibromin 1, Osteoblasts, Osteocytes, Osteogenesis, Phenotype, Porosity, Promoter Regions, Genetic, Recombination, Genetic, Stem Cells, ras Proteins
Show Abstract · Added November 14, 2013
Mutations in NF1 cause neurofibromatosis type I (NF1), a disorder characterized, among other clinical manifestations, by generalized and focal bony lesions. Dystrophic scoliosis and tibial pseudoarthrosis are the most severe skeletal manifestations for which treatment is not satisfactory, emphasizing the dearth of knowledge related to the biology of NF1 in bone cells. Using reporter mice, we report here that the mouse Col2α1-Cre promoter (collagen, type II, alpha 1) is active not only in chondrocytes but also in adult bone marrow osteoprogenitors giving rise to osteoblasts. Based on this finding, we crossed the Col2α1-Cre transgenic and Nf1(flox/flox) mice to determine whether loss of Nf1 in axial and appendicular osteochondroprogenitors recapitulates the skeletal abnormalities of NF1 patients. By microtomographic and X-rays studies, we show that Nf1(Col2)(-/-) mice display progressive scoliosis and kyphosis, tibial bowing and abnormalities in skull and anterior chest wall formation. These defects were accompanied by a low bone mass phenotype, high bone cortical porosity, osteoidosis, increased osteoclastogenesis and decreased osteoblast number, as quantified by histomorphometry and 3D-microtomography. Loss of Nf1 in osteochondroprogenitors also caused severe short stature and intervertebral disc defects. Blockade of the RAS/ERK activation characteristic of Nf1(-/-) osteoprogenitors by lovastatin during embryonic development could attenuate the increased cortical porosity observed in mutant pups. These data and the skeletal similarities between this mouse model and NF1 patients thus suggest that activation of the RAS/ERK pathway by Nf1 loss-of-function in osteochondroprogenitors is responsible for the vertebral and tibia lesions in NF1 patients, and that this molecular signature may represent a good therapeutic target.
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24 MeSH Terms
Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options.
Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA
(2009) Am J Med Genet A 149A: 2327-38
MeSH Terms: Animals, Bone Diseases, Developmental, Bone and Bones, Disease Models, Animal, Humans, Mice, Models, Biological, Neurofibromatosis 1, Sphenoid Bone, Thoracic Wall, Tibia
Show Abstract · Added November 14, 2013
The skeleton is frequently affected in individuals with neurofibromatosis type 1, and some of these bone manifestations can result in significant morbidity. The natural history and pathogenesis of the skeletal abnormalities of this disorder are poorly understood and consequently therapeutic options for these manifestations are currently limited. The Children's Tumor Foundation convened an International Neurofibromatosis Type 1 Bone Abnormalities Consortium to address future directions for clinical trials in skeletal abnormalities associated with this disorder. This report reviews the clinical skeletal manifestations and available preclinical mouse models and summarizes key issues that present barriers to optimal clinical management of skeletal abnormalities in neurofibromatosis type 1. These concepts should help advance optimal clinical management of the skeletal abnormalities in this disease and address major difficulties encountered for the design of clinical trials.
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11 MeSH Terms
ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae.
Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G
(2006) Cell Metab 4: 441-51
MeSH Terms: Activating Transcription Factor 4, Amino Acids, Animals, Biological Transport, Active, Bone Diseases, Developmental, Bone Resorption, Cell Differentiation, Coffin-Lowry Syndrome, Collagen, Cyclic AMP-Dependent Protein Kinases, Dietary Proteins, Mice, Mice, Knockout, Neurofibromin 1, Osteoblasts, Osteoclasts, Osteogenesis, RANK Ligand, Ribosomal Protein S6 Kinases, 90-kDa
Show Abstract · Added November 14, 2013
The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1(ob)(-/-) mice without affecting other organ weight, while a high-protein diet overcame Atf4(-/-) and Rsk2(-/-) mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.
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19 MeSH Terms
The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.
Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR
(2002) Mol Cell Biol 22: 3864-74
MeSH Terms: Animals, Apoptosis, Bone Development, Bone Diseases, Developmental, Cell Survival, Collagen Type I, Diabetes Mellitus, Endoplasmic Reticulum, Rough, Eukaryotic Initiation Factor-2, Gene Expression, Glucose, Growth Disorders, Humans, Mice, Mice, Knockout, Pancreas, Phosphorylation, eIF-2 Kinase
Show Abstract · Added January 6, 2014
Phosphorylation of eukaryotic initiation factor 2 alpha (eIF-2 alpha) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2 alpha (eIF-2 alpha[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2 alpha. Among the four eIF-2 alpha kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2 alpha[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk(-/-) mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk(-/-) mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.
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18 MeSH Terms
Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome).
Gorski JL, Estrada L, Hu C, Liu Z
(2000) Dev Dyn 218: 573-86
MeSH Terms: 3T3 Cells, Animals, Blotting, Northern, Bone Diseases, Developmental, Bone and Bones, Cells, Cultured, Face, Genetic Linkage, Genitalia, Guanine Nucleotide Exchange Factors, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mutation, Phenotype, Protein Biosynthesis, Proteins, RNA, Reverse Transcriptase Polymerase Chain Reaction, Syndrome, Transfection, Tumor Cells, Cultured, X Chromosome
Show Abstract · Added February 27, 2013
FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. To further define the role of FGD1 in skeletal development, we examined its expression in developing mouse embryos and correlated this pattern with FGDY skeletal defects. In this study, we show that Fgd1, the mouse FGD1 ortholog, is initially expressed during the onset of ossification during embryogenesis. Fgd1 is expressed in regions of active bone formation in the trabeculae and diaphyseal cortices of developing long bones. The onset of Fgd1 expression correlates with the expression of bone sialo-protein, a protein specifically expressed in osteoblasts at the onset of matrix mineralization; an analysis of serial sections shows that Fgd1 is expressed in tissues containing calcified and mineralized extracellular matrix. Fgd1 protein is specifically expressed in cultured osteoblast and osteoblast-like cells including MC3T3-E1 cells and human osteosarcoma cells but not in other mesodermal cells; immunohistochemical studies confirm the presence of Fgd1 protein in mouse calvarial cells. Postnatally, Fgd1 is expressed more broadly in skeletal tissue with expression in the perichondrium, resting chondrocytes, and joint capsule fibroblasts. The data indicate that Fgd1 is expressed in a variety of regions of incipient and active endochondral and intramembranous ossification including the craniofacial bones, vertebrae, ribs, long bones and phalanges. The observed pattern of Fgd1 expression correlates with FGDY skeletal manifestations and provides an embryologic basis for the prevalence of observed skeletal defects. The observation that the induction of Fgd1 expression coincides with the initiation of ossification strongly suggests that FGD1 signaling plays a role in ossification and bone formation; it also suggests that FGD1 signaling does not play a role in the earlier phases of skeletogenesis. With the observation that FGD1 mutations result in the skeletal dysplasia FGDY, accumulated data indicate that FGD1 signaling plays a critical role in ossification and skeletal development.
Copyright 2000 Wiley-Liss, Inc.
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25 MeSH Terms