Abnormal ossification in thanatophoric dysplasia

Horton, William A.; Hood, O. J.; Machado, Mirta A.; Ahmed, Saira; Griffey, E.S.

doi:10.1016/8756-3282(88)90027-0

Cited by 34 publications

(18 citation statements)

References 14 publications

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“…FGFR1 may be the best candidate for transducing the mitotic signals since it has been assigned this function in many cell types [33]. Similarly, FGFR3 may be the best candidate for transmitting signals that inhibit terminal differentiation since constitutive activation of FGFR3 is associated with markedly reduced terminal differentiation in the human dwarfing condition, thanatophoric dysplasia [9,34,35]. We have also observed a decrease in the number of hypertrophic chondrocytes in the growth plates of transgenic mice in which FGF9 was over-expressed in cartilage (S. Garofalo and W. A. Horton, unpublished work).…”

Section: Discussionmentioning

confidence: 99%

Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Weksler

Lunstrum

Reid

et al. 1999

Biochemical Journal

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Fibroblast growth factor (FGF) 9 was compared with FGF2 in its ability to influence proliferation, differentiation, terminal differentiation and apoptosis in a rat calvaria-derived cell line (RCJ 3.1C5.18) that spontaneously undergoes chondrocyte differentiation in vitro. Like FGF2, FGF9 promoted proliferation, but to a lesser extent. In contrast to FGF2, which blocked chondrocytic differentiation, FGF9 had no effect on differentiation but inhibited terminal differentiation. FGF9 also stimulated expression of the mitotic inhibitor p21 to a greater extent than FGF2. Neither ligand influenced apoptosis. The results indicate that FGF9 could account for many of the physiological responses attributed to FGF-receptor activation in the growth plate.

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Section: Discussionmentioning

confidence: 99%

Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Weksler

Lunstrum

Reid

et al. 1999

Biochemical Journal

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“…We infer that temporal-lobe dysmorphogenesis in TD begins between 11.5 weeks gestational age, when hippocampal and fimbriodentate fissure formation takes place, and 13.5 weeks gestational age, when differential proliferation and migration of the cells that form the pyramidal layer and the dentate gyrus takes place. Any etiology proposed for TD must not only account for disordered endochondral and endomembranous bone formation but also explain the origins of early temporal-lobe dysplasia.The external phenotype and skeletal abnormalities that characterize thanatophoric dysplasia (TD) are well known [1,2]. Associated abnormalities of the central nervous system have been described [3][4][5][6][7][8][9][10] in affected individuals ranging in age from the 23rd week of gesta tion [7] to term, and have been attributed to globally dis ordered central nervous system development [9].…”

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confidence: 99%

“…The brain weighed 41 g (expected [17], 23 g). The fetus met dysmorphologic criteria for TD [1] and sections of ossification fronts in a femur, vertebrae, and ribs met histopathologic criteria for TD [2]. Cultured amniocytes had a 46,XY chromosomal complement.…”

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confidence: 99%

Temporal-Lobe Abnormalities in Thanatophoric Dysplasia

Knisely

Ambler

1988

Pediatr Neurosurg

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We identified distinctive and characteristic abnormalities in the hippocampal formations of 4 individuals with thanatophoric dysplasia (TD), one of whom was a fetus of 19 weeks gestational age. Primitive medial fissures in this subject could be identified, but development of the dentate gyrus and organization of the pyramidal layer in the hippocampal formation were abnormal. We infer that temporal-lobe dysmorphogenesis in TD begins between 11.5 weeks gestational age, when hippocampal and fimbriodentate fissure formation takes place, and 13.5 weeks gestational age, when differential proliferation and migration of the cells that form the pyramidal layer and the dentate gyrus takes place. Any etiology proposed for TD must not only account for disordered endochondral and endomembranous bone formation but also explain the origins of early temporal-lobe dysplasia.

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“…[13][14][15][16][17] Qualitatively, most of these abnormalities were similar irrespective of the mutant genotype, including reduced height of proliferating and hypertrophic zones, irregular columnar arrangement, and decreased number and size of hypertrophic chondrocytes. In contrast, the resting chondrocyte zone looked normal.…”

Section: Growth Plate Abnormalities In Fetuses Carrying Fgfr3 Mutationsmentioning

confidence: 99%

“…12 Histologically, growth plates in ACH and TD patients present a specific disruption of their architecture, with a disorganization and shortness of the chondrocyte columns, and a reduced size of the hypertrophic zone. [13][14][15][16][17] Additional morphological abnormalities, including increased bone collar thickness, and presence of numerous large vascular canals have been reported. An inward extension of mesenchymal fibrous tissue from the perichondrium has been detected in TD, but not in ACH.…”

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confidence: 99%

Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

Cormier

Delezoide

Benoist-Lasselin

et al. 2002

The American Journal of Pathology

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The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans , FGFR3 signaling does not downregulate the main players of the IHH/PTHR1 pathway. Endochondral bone ossification is a highly regulated process involved in the formation and growth of cartilaginous templates of long bones, vertebrae, and some craniofacial bones. It requires the linear phenotypic progression of undifferentiated mesenchymal cells into hypertrophic chondrocytes and the subsequent replacement of mineralized cartilage matrix by bone.1-4 As part of this process, resting chondrocytes at the growth plate proliferate, then mature and differentiate into hypertrophic chondrocytes and finally undergo apoptosis after mineralization of the surrounding extracellular matrix. Lacunae formed in this way in the mineralized matrix are invaded by blood vessels and bone cells. At each stage, chondrocytes express specific markers including type 2 collagen in the resting, proliferative, and prehypertrophic zones, and type 10 collagen when hypertrophic.In addition to endochondral ossification, development and growth of bones formed via a cartilage model involve a distinct pattern of bone formation, namely perichondrial bone formation, 2,3,5 a process whereby bone is formed outside and around the cartilage anlage. When ossification starts, perichondrial ossification generates the primitive cortical bone (or bone collar) and its associated periosteum, and the bone-perichondrial ring that develops around the growth plate at the cartilage/bone junction. Bone-perichondrial ring (also called ossification groove of Ranvier) 5,6 comprises the bony ring (also called ring of Lacroix) 5,6 covered on the periosteal side by a loose connective tissue that acts as a germinative (cambium) layer, assuring growth in width. Its growth in length is insured by a germinative zone localized at the epiphyseal tip of the ring.Two main systems, namely the fibroblast growth factor receptor type 3 (FGFR3) and the Indian hedgehog (IHH)/

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Abnormal ossification in thanatophoric dysplasia

Cited by 34 publications

References 14 publications

Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Temporal-Lobe Abnormalities in Thanatophoric Dysplasia

Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

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