Constitutional Disorders of Skeletal Development: The Skeletal Dysplasias

Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype. There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations upregulated several anterior HOX genes and downregulated antioxidant genes CAT and GSTA1 throughout chondrogenesis. BMP4 treatment upregulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.

Download Full-text

Skeletal Dysplasias Reveal Genes of Importance in Skeletal Development and Structure

Connective Tissue Research ◽

10.1080/713713638 ◽

2003 ◽

Vol 44 (1) ◽

pp. 246-249

Author(s):

William Cole

Keyword(s):

Skeletal Development ◽

Skeletal Dysplasias

Download Full-text

Clinico – Radiological Study of Skeletal Dysplasias

Asian Journal of Medical Radiological Research ◽

10.47009/ajmrr.2020.8.1.30 ◽

2020 ◽

Vol 8 (1) ◽

pp. 166-171

Author(s):

B. Vanaja ◽

M Veena ◽

Shivaji Gogi

Keyword(s):

Skeletal Dysplasia ◽

Skeletal Development ◽

Biochemical Tests ◽

Radiological Study ◽

Skeletal Dysplasias ◽

Radiological Features ◽

The World ◽

Proper Diagnosis ◽

Different Parts

Background: Skeletal dysplasia and osteochondrodysplasia refer to a genetically and clinically heterogeneous group of disorders of skeletal development and growth. Their prevalence is about 1 in 4000 births. Skeletal dysplasia is prevalent worldwide and its prevalence varies in different parts of the world and even in the same country varies from region to region. The objective is to study the prevalence of skeletal dysplasia based on clinico-radiological features. Subjects and Methods: A hospital retro prospective based study of skeletal dysplasia’s was conducted over a period of 2 years in which 100 cases of skeletal dysplasia’s were studied and were grouped according to international classification of osteochondrodysplasia’ s revised in 2006. Results: 100 cases of skeletal dysplasia’s were detected by various modes of examination like clinical, radiological (radiographs, USG, CT scan, MRI, echocardiography), genetic and biochemical tests. Among 100 cases 22 cases showed clinico-radiologically concordance, 45 cases showed clinico-radiological complement and 40 cases showed clinico-radiological discordance. Conclusion: Our study makes an important observation that only clinical evaluation detected only 20% of skeletal dysplasia’s; and hence the importance of clinic-radiological evaluation in the proper diagnosis of skeletal dysplasia’s.

Download Full-text

Morphology and development of a novel murine skeletal dysplasia

PeerJ ◽

10.7717/peerj.7180 ◽

2019 ◽

Vol 7 ◽

pp. e7180

Author(s):

Marta Marchini ◽

Elizabeth Silva Hernandez ◽

Campbell Rolian

Keyword(s):

Skeletal Dysplasia ◽

Endochondral Ossification ◽

Skeletal Development ◽

Embryonic Stage ◽

Specific Cell ◽

Trabecular Thickness ◽

Skeletal Dysplasias ◽

Proliferative Zone ◽

Chondrogenic Marker ◽

Proliferation Assays

Background Limb bones develop and grow by endochondral ossification, which is regulated by specific cell and molecular pathways. Changes in one or more of these pathways can have severe effects on normal skeletal development, leading to skeletal dysplasias. Many skeletal dysplasias are known to result from mis-expression of major genes involved in skeletal development, but the etiology of many skeletal dysplasias remains unknown. We investigated the morphology and development of a mouse line with an uncharacterized mutation exhibiting a skeletal dysplasia-like phenotype (Nabo). Methods We used µCT scanning and histology to comprehensively characterize the phenotype and its development, and to determine the developmental stage when this phenotype first appears. Results Nabo mice have shorter limb elements compared to wildtype mice, while clavicles and dermal bones of the skull are not affected. Nabo embryos at embryonic stage E14 show shorter limb cartilage condensations. The tibial growth plate in Nabo mice is wider than in wildtype, particularly in the proliferative zone, however proliferative chondrocytes show less activity than wildtype mice. Cell proliferation assays and immunohistochemistry against the chondrogenic marker Sox9 suggest relatively lower, spatially-restricted, chondrocyte proliferation activity in Nabo. Bone volume and trabecular thickness in Nabo tibiae are also decreased compared to wildtype. Discussion Our data suggest that the Nabo mutation affects endochondral ossification only, with the strongest effects manifesting in more proximal limb structures. The phenotype appears before embryonic stage E14, suggesting that outgrowth and patterning processes may be affected. Nabo mice present a combination of skeletal dysplasia-like characteristics not present in any known skeletal dysplasia. Further genomic and molecular analysis will help to identify the genetic basis and precise developmental pathways involved in this unique skeletal dysplasia.

Download Full-text