Observations of growth plate development in achondroplastic (cn/cn) mice

Marco, Agustina

doi:10.1051/rnd:19810715

Cited by 6 publications

(7 citation statements)

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“…In cn/cn mice, the proliferative activities of proliferating chondrocytes in the epiphyseal growth plate are significantly lower than in control mice (25,26). The numbers of proliferating and hypertrophic chondrocytes are also severely reduced in cn/cn mice (17,18). The signal pathway through NPRB therefore appears to positively affect chondrocyte proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 91%

“…These phenotypes are distinguishable from normal littermates by 7 days after birth and thereafter gradually become more prominent (15,16). Histological analyses have revealed that the tibial epiphyseal growth plates of cn/cn mice are thinner than normal mice, and the hypertrophic chondrocyte zone is considerably narrowed (17,18). These findings suggested that the dwarf phenotype of cn/cn mouse was caused by retarded longitudinal bone growth due to disturbed endochondral ossification.…”

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confidence: 74%

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A Loss-of-Function Mutation in Natriuretic Peptide Receptor 2 (Npr2) Gene Is Responsible for Disproportionate Dwarfism in cn/cn Mouse

Tsuji

Kunieda

2005

Journal of Biological Chemistry

134

102

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The achondroplastic mouse is a spontaneous mutant characterized by disproportionate dwarfism with short limbs and tail due to disturbed chondrogenesis during endochondral ossification. These abnormal phenotypes are controlled by an autosomal recessive gene (cn). In this study, linkage analysis using 115 affected mice of F 2 progeny mapped the cn locus on an ϳ0.8-cM region of chromosome 4, and natriuretic peptide receptor 2 (Npr2) gene was identified as the most potent candidate for the cn mutant in this region. This gene encodes a receptor for C-type natriuretic peptide (CNP) that positively regulates longitudinal bone growth by producing cGMP in response to CNP binding to the extracellular domain. Sequence analyses of the Npr2 gene in cn/cn mice revealed a T to G transversion leading to the amino acid substitution of highly conserved Leu with Arg in the guanylyl cyclase domain. In cultured chondrocytes of cn/cn mice, stimulus with CNP did not significantly increase intracellular cGMP concentration, whereas it increased in ؉/؉ mice. Transfection of the mutant Npr2 gene into COS-7 cells also showed similar results, indicating that the missense mutation of the Npr2 gene in cn/cn mice resulted in disruption of the guanylyl cyclase activity of the receptor. We therefore concluded that the dwarf phenotype of cn/cn mouse is caused by a loss-offunction mutation of the Npr2 gene, and cn/cn mouse will be a useful model to further study the molecular mechanism regulating endochondral ossification by CNP/natriuretic peptide receptor B signal.The skeleton of vertebrates is formed by two different processes, namely intramembranous and endochondral ossifications. The latter process leads to the development of long bones that comprise the appendicular skeleton and vertebrae. During endochondral ossification, mesenchymal cells initially differentiate into chondrocytes, and progress through proliferating, maturating, and hypertrophic stages with strict columnar alignment. Distal hypertrophic chondrocytes then undergo apoptosis and are replaced by trabecular bone. A large number of genes have been implicated in the mechanisms regulating these processes (1), and mutations of these genes often cause skeletal dysplasias with shortened extremities (2, 3).The natriuretic peptide (NP) 1 family comprises atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) (4), and three receptors for NPs, including natriuretic peptide receptor A (NPRA), natriuretic peptide receptor B (NPRB), and natriuretic peptide receptor C (NPRC), have been identified in mammals (5-7). NPRA and NPRB consist of extracellular ligand binding, transmembrane, protein kinase homology, and guanylyl cyclase catalytic domains. These receptors mediate ligand signals by producing an intracellular second messenger, cyclic GMP (cGMP) (2). Both ANP and BNP bind to NPRA with high affinity, and CNP prefers binding to NPRB (8). NPRC has a ligand-binding domain and a short cytoplasmic domain that lacks guanylyl cyclase activity and i...

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 74%

A Loss-of-Function Mutation in Natriuretic Peptide Receptor 2 (Npr2) Gene Is Responsible for Disproportionate Dwarfism in cn/cn Mouse

Tsuji

Kunieda

2005

Journal of Biological Chemistry

134

102

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“…The data clearly indicate that ACH chondrocytes displayed a higher proliferative activity in respect of those from normal mice of the same age and under the same culture conditions. These results, confirmed also by a thymidine incorporation assay, were unexpected since previous studies reported that the main difference between achondroplastic mice and normal controls seems to be represented by anomalous evolution of ACH cell cartilage that leads to reduction of the hypertrophic zone ( De Marco 1981). It is well known that the endochondral ossification occurs during a series of successive steps:, i.e.…”

Section: Discussionmentioning

confidence: 53%

“…Further studies on development of the growth plate showed that the process of chondrocyte differentiation, occurring during their hypertrophy, is disturbed. In particular, the hypertrophic zone is reduced in mice cn/cn , probably because of a loss of cells ( De Marco 1981). No data on biochemical lesions in achondroplastic mice are known.…”

Section: Introductionmentioning

confidence: 99%

In vitro proliferation of achondroplastic and normal mouse chondrocytes, before and after basic fibroblast growth factor stimulation

Argentin

Cicchetti

2000

Cell Proliferation

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Achondroplasia in mice is a recessive genetic disorder, characterized by disproportionate dwarfism with reduced bone growth. The cause of this chondrodystrophy is unknown. In this study normal and achondroplastic mouse chondrocytes were cultured in monolayer primary culture, their differentiation was verified by immunofluorescence and their growth was compared. The results showed that achondroplastic cells exhibited a higher proliferative activity than control cells of the same age, confirmed also by a thymidine incorporation assay. Furthermore, basic fibroblast growth factor treatment was found to induce a strong increase in growth of normal mouse chondrocytes, while it did not stimulate statistically significant proliferation of achondroplastic mouse cells. We suppose that this different growth rate could play a role in achondroplastic phenotype development.

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“…Short stature, abnormal growth plate characteristics, and an autosomal recessive pattern were described in the initial report [ 1 ]. Slowed growth of the femur and tibia [ 2 ], abnormal histologic appearance of the growth plates [ 3 – 10 ], and extent of involvement of various regions of the physes [ 3 , 7 , 9 , 10 ] were defined. Affected cn/cn mice were only 60-70% the size of unaffected littermates, the bones that developed via the endochondral sequence were 60%-70% the length of normals with intramembranous bone unaffected, and in the histologically abnormal growth plates the shortened hypertrophic chondrocyte zone was the most affected part.…”

Section: Introductionmentioning

confidence: 99%

The cn/cn dwarf mouse. Histomorphometric, ultrastructural, and radiographic study in mutants corresponding to human acromesomelic dysplasia Maroteaux type (AMDM)

Shapiro

Barone

Johnson

et al. 2014

BMC Musculoskelet Disord

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BackgroundThe cn/cn dwarf mouse is caused by a loss-of-function mutation in the natriuretic peptide receptor 2 (NPR-2) gene which helps positively regulate endochondral longitudinal bone growth. The gene mutation corresponds to that in the human skeletal dysplasia Acromesomelic Dysplasia Maroteaux type (AMDM). This study assesses histomorphometric, ultrastructural and radiographic correlates of the growth abnormality.MethodsTen litters of cn/cn and cn/+littermates at ages ranging from 2.5 to 6.5 weeks were studied by skeletal radiographs, histomorphometry and physeal ultrastructure. Skeletal radiographs were done on 2 cn/cn and 2 cn/+littermates at 5 weeks of age. Humeral, femoral, and tibial lengths were measured from 34 intact bones (17 cn/cn, 17 cn/+) at 2.5 to 6.5 weeks. Growth plate histomorphometry in 50 bones (26 cn/cn and 24 cn/+) determined the hypertrophic zone/entire physeal cartilage ratios in 204 sections (87 cn/+, 117 cn/cn) at 3 time periods (2.5-3, 4–4.5, and 6–6.5 weeks). Electron microscopy assessed 6 cn/cn and 6 cn/+age and site-matched physeal cartilage.ResultsCn/cn mice were two thirds the size of the cn/+. Cn/cn bones were normal in shape or only minimally deformed except for the radius with mid-diaphyseal bowing. Length ratios of cn/cn humeri, femurs, and tibias were a mean of 0.65 (±0.03, n = 34, 17 ratios) compared to cn/+bones. The main physeal abnormality was a markedly shortened hypertrophic zone with the ratio of hypertrophic zone to entire physis 0.17 (±0.063) in the cn/cn and 0.30 (±0.052) in the cn/+mice. Ratio assessments were similar comparing humeral, femoral, and tibial growth plates as were ratios from each of the 3 time periods. Ultrastructural assessments from the resting zone to the lower hypertrophic zone-metaphyseal junction showed no specific individual cell abnormalities in cn/cn compared to cn/+physes.ConclusionsThe disorder causes a shortened physeal hypertrophic zone but normal ultrastructure of cn/cn chondrocytes points to abnormality primarily affecting the hypertrophic zone rather than a structural cell or matrix synthesis problem.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-347) contains supplementary material, which is available to authorized users.

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Observations of growth plate development in achondroplastic (cn/cn) mice

Abstract: Summary. The autosomal recessive gene for achondroplasia (cn)

Cited by 6 publications

References 12 publications

A Loss-of-Function Mutation in Natriuretic Peptide Receptor 2 (Npr2) Gene Is Responsible for Disproportionate Dwarfism in cn/cn Mouse

A Loss-of-Function Mutation in Natriuretic Peptide Receptor 2 (Npr2) Gene Is Responsible for Disproportionate Dwarfism in cn/cn Mouse

In vitro proliferation of achondroplastic and normal mouse chondrocytes, before and after basic fibroblast growth factor stimulation

The cn/cn dwarf mouse. Histomorphometric, ultrastructural, and radiographic study in mutants corresponding to human acromesomelic dysplasia Maroteaux type (AMDM)

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