Achondrogenesis Type IA (Houston-Harris): A Still-Unresolved Molecular Phenotype

2007 ◽  
Vol 10 (4) ◽  
pp. 328-334 ◽  
Author(s):  
Thomas Aigner ◽  
Tilman Rau ◽  
Manuel Niederhagen ◽  
Frank Zaucke ◽  
Markus Schmitz ◽  
...  
Keyword(s):  
Ultrastructural Level ◽  
Cartilage Matrix ◽  
Endochondral Bone Formation ◽  
Matrix Assembly ◽  
Endochondral Bone ◽  
Zone Formation ◽  
Chondrocyte Maturation ◽  
Oligomeric Protein ◽  
Type Ia ◽  
Achondrogenesis Type

Achondrogenesis type IA (Houston-Harris) is an extremely rare lethal chondrodysplasia with a characteristic severe disarrangement of endochondral ossification. The growth plate cartilage completely lacks columnar-zone formation and shows chondrocyte expansion due to intracellular vacuoles. This article on a new case of achondrogenesis type IA confirms these findings and demonstrates, on the ultrastructural level, the retention of fine fibrillar material within the rough endoplasmic reticulum (rER). Molecular analysis in the presented case of achondrogenesis type IA did not reveal mutations in the COL2A1 and SLC26A2 genes, which are known to cause achondrogenesis types IB and type II. Although the extracellular cartilage matrix was severely altered, all of the investigated matrix molecules (collagens, aggrecan, matrilins, cartilage oligomeric protein [COMP]) showed a normal distribution pattern. The only exception was type-X collagen, which was significantly reduced. Overall, our study suggests a disturbance in cartilage matrix assembly in the present case due to the retention of some sort of matrix component within the rER. Presumably, as a consequence of this event, processes of chondrocyte maturation and differentiation and endochondral bone formation are severely affected in this case of achondrogenesis type IA.

Achondrogenesis Type IB

2001 ◽  
Vol 125 (10) ◽  
pp. 1375-1378
Author(s):  
Alessandro Corsi ◽  
Mara Riminucci ◽  
Larry W. Fisher ◽  
Paolo Bianco
Keyword(s):  
Cartilage Matrix ◽  
Endochondral Bone Formation ◽  
Transporter Gene ◽  
Sulfate Transporter ◽  
Matrix Assembly ◽  
Endochondral Bone ◽  
Skeletal Phenotype ◽  
Matrix Organization ◽  
Achondrogenesis Type ◽  
Sulfate Transporter Gene

Abstract Achondrogenesis type IB is a lethal osteochondrodysplasia caused by mutations in the diastrophic dysplasia sulfate transporter gene. How these mutations lead to the skeletal phenotype is not known. Histology of plastic-embedded skeletal fetal achondrogenesis type IB samples suggested that interterritorial epiphyseal cartilage matrix was selectively missing. Cartilage was organized in “chondrons” separated by cleft spaces; chondrocyte seriation, longitudinal septa, and, in turn, mineralized cartilaginous septa were absent. Agenesis of interterritorial matrix as the key histologic change was confirmed by immunohistology using specific markers of territorial and interterritorial matrix. Biglycan-enriched territorial matrix was preserved; decorin-enriched interterritorial areas were absent, although immunostaining was observed within chondrocytes. Thus, in achondrogenesis type IB: (1) a complex derangement in cartilage matrix assembly lies downstream of the deficient sulfate transporter activity; (2) the severely impaired decorin deposition participates in the changes in matrix organization with lack of development of normal interterritorial matrix; and (3) this change determines the lack of the necessary structural substrate for proper endochondral bone formation and explains the severe skeletal phenotype.

Achondrogenesis

2007 ◽  
Vol 10 (4) ◽  
pp. 253-255 ◽  
Author(s):  
Raj P. Kapur
Keyword(s):  
Cartilage Matrix ◽  
Genotypic Differences ◽  
Skeletal Dysplasias ◽  
Type Ia ◽  
Achondrogenesis Type ◽  
Insight Into ◽  
Developmental Pathology

In this issue of Pediatric and Developmental Pathology, Aigner and colleagues report a detailed investigation of cartilage matrix changes in a 14-week fetus with achondrogenesis type IA [ 1 ]. The changes reported differ from matrix alterations observed in achondrogenesis types IB or II and provide insight into the phenotypic and genotypic differences within this group of skeletal dysplasias.

scholarly journals Selective Deficiency of the “Bone-related”Runx2-II Unexpectedly Preserves Osteoblast-mediated Skeletogenesis

2004 ◽  
Vol 279 (19) ◽  
pp. 20307-20313 ◽  
Author(s):  
Zhou-Sheng Xiao ◽  
Anita B. Hjelmeland ◽  
L. D. Quarles
Keyword(s):  
Bone Formation ◽  
Ex Vivo ◽  
Mesenchymal Cells ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Chondrocyte Maturation ◽  
Intramembranous Bone ◽  
Exon 1 ◽  
Metaphyseal Bone ◽  
Deficient Mice

Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the “bone-related”Runx2-II and non-osseousRunx2-I isoforms that differ only in their respective N termini. Existing mutant mouse models with both isoforms deleted exhibit an arrest of osteoblast and chondrocyte maturation and the complete absence of mineralized bone, but they do not distinguish the separate functions of the two N-terminal isoforms. To elucidate the function of the bone-related isoform, we generated selectiveRunx2-II-deficient mice by the targeted deletion of the distal promoter and exon 1. HomozygousRunx2-II-deficient (Runx2-II-/-) mice unexpectedly formed axial, appendicular, and craniofacial bones derived from either intramembranous ossification or mesenchymal cells of the bone collar, but they failed to form the posterior cranium and other bones derived from endochondral ossification. HeterozygousRunx2-II-deficient mice had grossly normal skeletons, but were osteopenic. The commitment of mesenchymal cellsex vivoto the osteoblast lineage occurred inRunx2-II-/-mice, but osteoblastic gene expression was impaired. Chondrocyte maturation appeared normal, but the zone of hypertrophic chondrocytes was not transformed into metaphyseal bone, leading to widened growth plates inRunx2-II-/-mice. Compensatory increments inRunx2-I expression occurred inRunx2-II-/-mice but were not sufficient to normalize osteoblastic maturation or transcriptional activity. Our findings support distinct functions ofRunx2-II and -I in the control of skeletogenesis.Runx2-I is sufficient for early osteoblastogenesis and intramembranous bone formation, whereasRunx2-II is necessary for complete osteoblastic maturation and endochondral bone formation.

scholarly journals Association of an extracellular protein (chondrocalcin) with the calcification of cartilage in endochondral bone formation.

1984 ◽  
Vol 98 (1) ◽  
pp. 54-65 ◽  
Author(s):  
A R Poole ◽  
I Pidoux ◽  
A Reiner ◽  
H Choi ◽  
L C Rosenberg
Keyword(s):  
Extracellular Matrix ◽  
Bone Formation ◽  
Growth Plate ◽  
Calcium Binding ◽  
Calcium Binding Protein ◽  
Cartilage Matrix ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Nucleation Sites

We examined bovine fetal epiphyseal and growth plate cartilages by immunofluorescence microscopy and immunoelectron microscopy using monospecific antibodies to a newly discovered cartilage-matrix calcium-binding protein that we now call chondrocalcin. Chondrocalcin was evenly distributed at relatively low concentration in resting fetal epiphyseal cartilage. In growth plate cartilage, it was absent from the extracellular matrix in the zone of proliferating chondrocytes but was present in intracellular vacuoles in proliferating, maturing and upper hypertrophic chondrocytes. The protein then disappeared from the lower hypertrophic chondrocytes and appeared in the adjoining extracellular matrix, where it was selectively concentrated in the longitudinal septa in precisely the same location where amorphous mineral was deposited in large amounts as demonstrated by von Kossa staining and electron microscopy. Mineral then spread out from these "nucleation sites" to occupy much of the surrounding matrix. Matrix vesicles were identified in this calcifying matrix but they bore no observable morphological relationship to these major sites of calcification where chondrocalcin was concentrated. Since chondrocalcin is a calcium-binding protein and has a strong affinity for hydroxyapatite, these observations suggest that chondrocalcin may play a fundamental role in the creation of nucleation sites for the calcification of cartilage matrix in endochondral bone formation.

scholarly journals Constitutive E2F1 Overexpression Delays Endochondral Bone Formation by Inhibiting Chondrocyte Differentiation

2003 ◽  
Vol 23 (10) ◽  
pp. 3656-3668 ◽  
Author(s):  
Blanca Scheijen ◽  
Marieke Bronk ◽  
Tiffany van der Meer ◽  
René Bernards
Keyword(s):  
Bone Formation ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Late Phase ◽  
Type Ii Collagen ◽  
Endochondral Bone Formation ◽  
Nodule Formation ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Chondrocyte Maturation

ABSTRACT Longitudinal bone growth results from endochondral ossification, a process that requires proliferation and differentiation of chondrocytes. It has been shown that proper endochondral bone formation is critically dependent on the retinoblastoma family members p107 and p130. However, the precise functional roles played by individual E2F proteins remain poorly understood. Using both constitutive and conditional E2F1 transgenic mice, we show that ubiquitous transgene-driven expression of E2F1 during embryonic development results in a dwarf phenotype and significantly reduced postnatal viability. Overexpression of E2F1 disturbs chondrocyte maturation, resulting in delayed endochondral ossification, which is characterized by reduced hypertrophic zones and disorganized growth plates. Employing the chondrogenic cell line ATDC5, we investigated the effects of enforced E2F expression on the different phases of chondrocyte maturation that are normally required for endochondral ossification. Ectopic E2F1 expression strongly inhibits early- and late-phase differentiation of ATDC5 cells, accompanied by diminished cartilage nodule formation as well as decreased type II collagen, type X collagen, and aggrecan gene expression. In contrast, overexpression of E2F2 or E2F3a results in only a marginal delay of chondrocyte maturation, and increased E2F4 levels have no effect. These data are consistent with the notion that E2F1 is a regulator of chondrocyte differentiation.

scholarly journals Cooperation between p27 and p107 during Endochondral Ossification Suggests a Genetic Pathway Controlled by p27 and p130

2007 ◽  
Vol 27 (14) ◽  
pp. 5161-5171 ◽  
Author(s):  
Nancy Yeh ◽  
Jeffrey P. Miller ◽  
Tripti Gaur ◽  
Terence D. Capellini ◽  
Janko Nikolich-Zugich ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Gene Families ◽  
Cell Types ◽  
Mutant Mice ◽  
Endochondral Bone Formation ◽  
Cell Type ◽  
Mouse Development ◽  
Ectopic Ossification ◽  
Endochondral Bone ◽  
Chondrocyte Maturation

ABSTRACT Pocket proteins and cyclin-dependent kinase (CDK) inhibitors negatively regulate cell proliferation and can promote differentiation. However, which members of these gene families, which cell type they interact in, and what they do to promote differentiation in that cell type during mouse development are largely unknown. To identify the cell types in which p107 and p27 interact, we generated compound mutant mice. These mice were null for p107 and had a deletion in p27 that prevented its binding to cyclin-CDK complexes. Although a fraction of these animals survived into adulthood and looked similar to single p27 mutant mice, a larger number of animals died at birth or within a few weeks thereafter. These animals displayed defects in chondrocyte maturation and endochondral bone formation. Proliferation of chondrocytes was increased, and ectopic ossification was observed. Uncommitted mouse embryo fibroblasts could be induced into the chondrocytic lineage ex vivo, but these cells failed to mature normally. These results demonstrate that p27 carries out overlapping functions with p107 in controlling cell cycle exit during chondrocyte maturation. The phenotypic similarities between p107 −/− p27 D51/D51 and p107 −/− p130 −/− mice and the cells derived from them suggest that p27 and p130 act in an analogous pathway during chondrocyte maturation.

scholarly journals Retinoid Signaling Is Required for Chondrocyte Maturation and Endochondral Bone Formation during Limb Skeletogenesis

1999 ◽  
Vol 208 (2) ◽  
pp. 375-391 ◽  
Author(s):  
Eiki Koyama ◽  
Eleanor B. Golden ◽  
Thorsten Kirsch ◽  
Sherrill L. Adams ◽  
Roshantha A.S. Chandraratna ◽  
...  
Keyword(s):  
Bone Formation ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Retinoid Signaling ◽  
Chondrocyte Maturation

scholarly journals Ovotransferrin and ovotransferrin receptor expression during chondrogenesis and endochondral bone formation in developing chick embryo

1994 ◽  
Vol 124 (4) ◽  
pp. 579-588 ◽  
Author(s):  
C Gentili ◽  
R Doliana ◽  
P Bet ◽  
G Campanile ◽  
A Colombatti ◽  
...  
Keyword(s):  
Chick Embryo ◽  
Bone Formation ◽  
Blot Analysis ◽  
Receptor Expression ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Metabolic Labeling ◽  
Matrix Assembly ◽  
Endochondral Bone ◽  
Low Level

Ovotransferrin expression during chick embryo tibia development has been investigated in vivo by immunocytochemistry and in situ hybridization. Ovotransferrin was first observed in the 7 day cartilaginous rudiment. At later stages, the factor was localized in the articular zone of the bone epiphysis and in the bone diaphysis where it was concentrated in hypertrophic cartilage, in zones of cartilage erosion and in the osteoid at the chondro-bone junction. When the localization of the ovotransferrin receptors was investigated, it was observed that chondrocytes at all stages of differentiation express a low level of the oviduct (tissue) specific receptor. Interestingly, high levels of the receptor were detectable in the 13-d old tibia in the diaphysis collar of stacked-osteoprogenitor cells and in the layer of derived osteoblasts. High levels of oviduct receptor were also observed in the primordia of the menisci. Metabolic labeling of proteins secreted by cultured chondrocytes and osteoblasts and Northern blot analysis of RNA extracted from the same cells confirmed and completed the above information. Ovotransferrin was expressed by in vitro differentiating chondrocytes in the early phase of the culture and, at least when culture conditions allowed extracellular matrix assembly, also by hypertrophic chondrocytes and derived osteoblast-like cells. Osteoblasts directly obtained from bone chips produced ovotransferrin only at the time of culture mineralization. By Western blot analysis, oviduct receptor proteins were detected at a very low level in extract from differentiating and hypertrophic chondrocytes and at a higher level in extract from hypertrophic chondrocytes undergoing differentiation to osteoblast-like cells and from mineralizing osteoblasts. Based on these results, the existence of autocrine and paracrine loops involving ovotransferrin and its receptor during chondrogenesis and endochondral bone formation is discussed.

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