Short Rib Polydactyly Syndrome Type III: Histopathogenesis of the Skeletal Phenotype

A morphological study of the skeletal system in a case of short rib polydactyly syndrome type III (SRPS-III) documented a “bajonet” deformity of the ribs for misalignment and overlap of cartilaginous and bony ends. This deformity resulted from a ‘tandem’ change in endochondral bone formation that is, arrested orthotopic cartilage maturation and etherotopic perichondral cartilage differention and ossification. At the cartilaginous end, cartilage maturation and vascular invasion were absent. At the bony end, longitudinal bone growth occurred by a perichondral ectopic growth plate. ‘Miniature’ versions of this ‘tandem’ change were also demonstrated in the long bones of the limbs and included focally arrested orthotopic cartilage maturation at the growth plates, perichondral cartilage differentiation, and ossification within cartilage canals. Our morphological study indicates that a generalized loss of syncrony in cartilage removal and osteogenic differentiation occurs in all growth plates, albeit with varied expressivity, and represents, at tissue level, the mechanism by which the SRPS-III skeletal phenotype develops.

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Haploinsufficiency of osterix in chondrocytes impairs skeletal growth in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00111.2013 ◽

2013 ◽

Vol 45 (19) ◽

pp. 917-923 ◽

Cited By ~ 12

Author(s):

Shaohong Cheng ◽

Weirong Xing ◽

Xin Zhou ◽

Subburaman Mohan

Keyword(s):

Bone Growth ◽

Skeletal Growth ◽

Endochondral Bone Formation ◽

Volumetric Bone Mineral Density ◽

Mineral Density ◽

Endochondral Bone ◽

Alizarin Red ◽

Adult Mice ◽

Elevated Expression ◽

Skeletal Phenotype

Osterix ( Osx) is essential for both intramembranous or endochondral bone formation. Osteoblast-specific ablation of Osx using Col1α1-Cre resulted in osteopenia, because of impaired osteoblast differentiation in adult mice. Since Osx is also known to be expressed in chondrocytes, we evaluated the role of Osx expressed in chondrocytes by examining the skeletal phenotype of mice with conditional disruption of Osx in Col2α1-expressing chondrocytes. Surprisingly, Cre-positive mice that were homozygous for Osx floxed alleles died after birth. Alcian blue and alizarin red staining revealed that the lengths of skeleton, femur, and vertebrae were reduced by 21, 26, and 14% ( P < 0.01), respectively, in the knockout (KO) compared with wild-type mice. To determine if haploid insufficiency of Osx in chondrocytes influenced postnatal skeletal growth, we compared skeletal phenotype of floxed heterozygous mice that were Cre-positive or Cre-negative. Body length was reduced by 8% ( P < 0.001), and areal BMD of total body, femur, and tibia was reduced by 5, 7, and 8% ( P < 0.05), respectively, in mice with conditional disruption of one allele of Osx in chondrocytes. Micro-CT showed reduced cortical volumetric bone mineral density and trabecular bone volume to total volume in the femurs of Osxflox/+; col2α1-Cre mice. Histological analysis revealed that the impairment of longitudinal growth was associated with disrupted growth plates in the Osxflox/+; col2α1-Cre mice. Primary chondrocytes isolated from KO embryos showed reduced expression of chondral ossification markers but elevated expression of chondrogenesis markers. Our findings indicate that Osx expressed in chondrocytes regulates bone growth in part by regulating chondrocyte hypertrophy.

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DYNC2H1 Mutations Cause Asphyxiating Thoracic Dystrophy and Short Rib-Polydactyly Syndrome, Type III

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2009.04.016 ◽

2009 ◽

Vol 84 (5) ◽

pp. 706-711 ◽

Cited By ~ 155

Author(s):

Nathalie Dagoneau ◽

Marie Goulet ◽

David Geneviève ◽

Yves Sznajer ◽

Jelena Martinovic ◽

...

Keyword(s):

Syndrome Type ◽

Type Iii ◽

Asphyxiating Thoracic Dystrophy ◽

Short Rib Polydactyly Syndrome ◽

Thoracic Dystrophy

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Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

Clinica Chimica Acta ◽

10.1016/j.cca.2015.05.005 ◽

2015 ◽

Vol 447 ◽

pp. 47-51 ◽

Cited By ~ 12

Author(s):

Libin Mei ◽

Yanru Huang ◽

Qian Pan ◽

Wei Su ◽

Yi Quan ◽

...

Keyword(s):

Next Generation Sequencing ◽

Compound Heterozygous ◽

Syndrome Type ◽

Next Generation ◽

Type Iii ◽

Targeted Next Generation Sequencing ◽

Compound Heterozygous Mutations ◽

Short Rib Polydactyly Syndrome ◽

Generation Sequencing

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Chondrocytes Play a Major Role in the Stimulation of Bone Growth by Thyroid Hormone

Endocrinology ◽

10.1210/en.2014-1109 ◽

2014 ◽

Vol 155 (8) ◽

pp. 3123-3135 ◽

Cited By ~ 25

Author(s):

Clémence Desjardin ◽

Cyril Charles ◽

Catherine Benoist-Lasselin ◽

Julie Riviere ◽

Mailys Gilles ◽

...

Keyword(s):

Thyroid Hormone ◽

Bone Growth ◽

Cell Types ◽

Postnatal Growth ◽

Dominant Negative ◽

Skeletal Growth ◽

Endochondral Bone Formation ◽

Endochondral Bone ◽

Phenotype Analysis ◽

Visible Effect

Thyroid hormone (T3) is required for postnatal skeletal growth. It exerts its effect by binding to nuclear receptors, TRs including TRα1 and TRβ1, which are present in most cell types. These cell types include chondrocytes and osteoblasts, the interactions of which are known to regulate endochondral bone formation. In order to analyze the respective functions of T3 stimulation in chondrocytes and osteoblasts during postnatal growth, we use Cre/loxP recombination to express a dominant-negative TRα1L400R mutant receptor in a cell-specific manner. Phenotype analysis revealed that inhibiting T3 response in chondrocytes is sufficient to reproduce the defects observed in hypothyroid mice, not only for cartilage maturation, but also for ossification and mineralization. TRα1L400R in chondrocytes also results in skull deformation. In the meantime, TRα1L400R expression in mature osteoblasts has no visible effect. Transcriptome analysis identifies a number of changes in gene expression induced by TRα1L400R in cartilage. These changes suggest that T3 normally cross talks with several other signaling pathways to promote chondrocytes proliferation, differentiation, and skeletal growth.

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Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing

Genetics and Molecular Research ◽

10.4238/gmr.15028134 ◽

2016 ◽

Vol 15 (2) ◽

Cited By ~ 6

Author(s):

L.S. Chen ◽

S.J. Shi ◽

P.S. Zou ◽

M. Ma ◽

X.H. Chen ◽

...

Keyword(s):

Syndrome Type ◽

Next Generation ◽

Type Iii ◽

Short Rib Polydactyly Syndrome ◽

Panel Sequencing

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Sonographic detection of situs inversus, ventricular septal defect, and short-rib polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus not known to be at risk

Ultrasound in Obstetrics and Gynecology ◽

10.1046/j.1469-0705.2002.00731_4.x ◽

2002 ◽

Vol 19 (6) ◽

pp. 629-631 ◽

Cited By ~ 8

Author(s):

C.-P. Chen ◽

T.-Y. Chang ◽

C.-Y. Tzen ◽

C.-J Lin ◽

W. Wang

Keyword(s):

At Risk ◽

Ventricular Septal Defect ◽

Situs Inversus ◽

Septal Defect ◽

Syndrome Type ◽

Second Trimester ◽

Type Iii ◽

Short Rib Polydactyly Syndrome

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Glycogen synthase kinase 3 alpha/beta deletion induces precocious growth plate remodeling and cell loss in mice

10.1101/2020.04.04.025700 ◽

2020 ◽

Author(s):

Supinder Kour Bali ◽

Dawn Bryce ◽

Carina Prein ◽

James R. Woodgett ◽

Frank Beier

Keyword(s):

Articular Cartilage ◽

Growth Plate ◽

Bone Growth ◽

Glycogen Synthase ◽

Final Height ◽

Glycogen Synthase Kinase ◽

Metabolic Phenotype ◽

Endochondral Bone ◽

Growth Plates

ABSTRACTGlycogen synthase kinase (GSK) 3 acts to negatively regulate multiple signaling pathways, including canonical Wnt signaling. The two mammalian GSK3 proteins (alpha and beta) are at least partially redundant. While Gsk3a KO mice are viable and display a metabolic phenotype, abnormal neuronal development and accelerated aging, Gsk3b KO animals die late in embryogenesis or at birth. Selective Gsk3b KO in bone delayed development of some bones, whereas cartilage-specific Gsk3b KO mice are normal except for elevated levels of GSK3alpha protein. However, the collective role of these two GSK3 proteins in cartilage was not evaluated. To address this, we generated tamoxifen-inducible, cartilage-specific Gsk3a/Gsk3b KO in juvenile mice and investigated their skeletal phenotypes. We found that cartilage-specific Gsk3a/Gsk3b deletion in young, skeletally immature mice causes precocious growth plate remodeling, culminating in shorter long bones and hence, growth retardation. These mice exhibit inefficient breathing patterns at later stages and fail to survive. The disrupted growth plates in KO mice showed progressive loss of cellular and proteoglycan components and Sox9 positive cells, with increased staining for osteocalcin and type II collagen. In addition, an increase in osteoclast recruitment and cell apoptosis was observed in growth plates. Surprisingly, changes in articular cartilage of Gsk3a/Gsk3b KO mice were mild compared to growth plates, signifying differential regulation of articular cartilage vs growth plate tissues. Taken together, these findings emphasize a crucial role of two GSK3 proteins in skeletal development, in particular in the maintenance and function of growth plates.SignificanceGrowth plate cartilage dynamics determine the rate of endochondral bone growth and thus, our final height. These processes are disturbed in many genetic and acquired diseases, but the intracellular mechanisms responsible for normal growth plate function, as well as the cessation of growth plate activity in puberty, are poorly understood. Here, we demonstrate that specific removal of both GSK3 genes (Gsk3a and Gsk3b) in postnatal cartilage of mice leads to a severe reduction of endochondral bone growth, premature remodelling of the growth plate, and early death. In contrast, articular cartilage is only mildly affected by deletion of both genes. These studies identify GSK3 signaling as a key regulator of growth plate dynamics and endochondral bone growth.

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Achondrogenesis Type IB

Archives of Pathology & Laboratory Medicine ◽

10.5858/2001-125-1375-ati ◽

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.

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