Bone Abstracts

Cysteine-rich with EGF like domains 2 (Creld2) has recently been identified as an endoplasmic reticulum (ER) stress inducible gene in the context of skeletal dysplasia caused by mutant protein accumulating in the ER eliciting an unfolded protein response (UPR). Creld2 was originally implicated in ER stress following the treatment of Neuro2α cells with thapsigargin. Furthermore, the promoter of Creld2 contains an ER stress activating transcription factor 6 (ATF6) response element. The function of Creld2 is largely unknown despite various roles being identified 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 (MSC) osteogenic differentiation.

In order to determine the specific role of Creld2 in bone development and homeostasis, conditional Creld2 knockout mouse models were generated. Floxed Creld2 mice were bred onto Cre mice to generate cartilage (Col II-Cre) or bone (OC-Cre) -specific knockout mice.

Recent work has shown that cartilage-specific Creld2 knockout mice display disproportionate short statue and a disrupted cartilage growth plate with reduced chondrocyte proliferation. Preliminary phenotyping of the bone-specific Creld2 knockout model has shown that mice develop osteopenia potentially due to an increase in the number of osteoclasts.

The work presented here shows that Creld2 plays distinct roles in bone and cartilage as cartilage-specific knockout mice are significantly smaller and bone-specific knockout mice have a lower bone density. Future work will focus on underpinning the genetic and signalling changes following the ablation of Creld2 in order to gain a deeper understanding of its role in bone formation and growth.