Dwarfism in Homozygous Agc1CreERT Mice is Associated with Decreased Expression of Aggrecan

Aggrecan (Acan), a large proteoglycan is abundantly expressed in cartilage tissue. Disruption of Acan gene causes dwarfism and perinatal lethality of homozygous mice. Because of sustained expression of Acan in the growth plate and articular cartilage, Agc(Cre) model has been developed for the regulated ablation of target gene in chondrocytes. In this model, the IRES-CreERT-Neo-pgk transgene is knocked-in the 3'UTR of the Acan gene. We consistently noticed variable weight and size among the Agc(Cre) littermates, prompting us to examine the cause of this phenotype. Wild-type, Cre-heterozygous (Agc(+/Cre)), and Cre-homozygous (Agc(Cre/Cre)) littermates were indistinguishable at birth. However, by 1-month, Agc(Cre/Cre) mice showed a significant reduction in body weight (18-27%) and body length (19-22%). Low body weight and dwarfism was sustained through adulthood and occurred in both genders. Compared with wild-type and Agc(+/Cre) littermates, long bones and vertebrae were shorter in Agc(Cre/Cre) mice. Histological analysis of Agc(Cre/Cre) mice revealed a significant reduction in the length of the growth plate and the thickness of articular cartilage. The amount of proteoglycan deposited in the cartilage of Agc(Cre/Cre) mice was nearly half of the WT littermates. Analysis of gene expression indicates impaired differentiation of chondrocyte in hyaline cartilage of Agc(Cre/Cre) mice. Notably, both Acan mRNA and protein was reduced by 50% in Agc(Cre/Cre) mice. A strong correlation was noted between the level of Acan mRNA and the body length. Importantly, Agc(+/Cre) mice showed no overt skeletal phenotype. Thus to avoid misinterpretation of data, only the Agc(+/Cre) mice should be used for conditional deletion of a target gene in the cartilage tissue.