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Title: The role of cysteine rich with epidermal growth factor-like domains 2 in skeletal development and homeostasis
Author: Dennis, Ella Patricia
ISNI:       0000 0004 7961 0863
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2018
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Cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) has previously been identified as a genotype-specific endoplasmic reticulum (ER) stress-inducible gene implicated in the pathogenesis of skeletal dysplasias. The function of Creld2 is largely unknown despite putative roles described in protein folding and trafficking. Creld2 is expressed in mouse embryonic skeletal tissues and interestingly a novel role has been identified for Creld2 in mesenchymal stem cell osteogenic differentiation. To further study the role of Creld2 in skeletal development and homeostasis, conditional Creld2 knockout mice were generated and phenotyped. The data presented in this thesis revealed that cartilage-specific Creld2 knockout mice display a distinctive chondrodysplasia phenotype characterised by disproportionate short statue and a disrupted cartilage growth plate. The ablation of Creld2 in the growth plate significantly reduces chondrocyte differentiation, proliferation and survival resulting in regions of hypocellularity. Interestingly, analysis of the growth plate shows a striking misalignment of chondrocytes within individual chondrons would result from the impaired organisation of primary non-motile cilia. CRELD2 binds to low density lipoprotein receptor-related protein 1 (LRP1) in chondrocytes and it can therefore be hypothesised that CRELD2 plays a role in chondrocyte differentiation by modulating LRP1 trafficking. This study also focused on generating and phenotyping bone-specific Creld2 knockout mice. These mice display an osteopenic phenotype characterised by a reduction in bone mass, with impaired bone microarchitecture. The deletion of Creld2 in osteoblasts significantly impairs osteoblast differentiation and activity and interestingly induces the upregulation of osteoblast-derived osteoclastogenic cytokine production, disrupting the balance between bone formation and resorption indicating that CRELD2 plays an anabolic role in osteoblasts. Therefore Creld2 plays distinct roles in bone and cartilage and points to an important role for Creld2 in chondrocyte differentiation, osteoblast function and skeletal development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available