Dwarfism in homozygous Agc1 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 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 littermates, prompting us to examine the cause of this phenotype. Wild-type, Cre-heterozygous (Agc ), and Cre-homozygous (Agc ) littermates were indistinguishable at birth. However, by 1-month, Agc 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 littermates, long bones and vertebrae were shorter in Agc mice. Histological analysis of Agc 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 mice was nearly half of the WT littermates. Analysis of gene expression indicates impaired differentiation of chondrocyte in hyaline cartilage of Agc mice. Notably, both Acan mRNA and protein was reduced by 50% in Agc mice. A strong correlation was noted between the level of Acan mRNA and the body length. Importantly, Agc mice showed no overt skeletal phenotype. Thus to avoid misinterpretation of data, only the Agc mice should be used for conditional deletion of a target gene in the cartilage tissue.