Abstract
One of the goals of systems genetics is the reconstruction of gene networks that underlie key processes in development and disease. To identify cartilage gene networks that play an important role in bone development, we used a systems genetics approach that integrated microarray gene expression profiles from cartilage and bone phenotypic data from two sets of recombinant inbred strains. Microarray profiles generated from isolated chondrocytes were used to generate weighted gene coexpression networks. This analysis resulted in the identification of subnetworks (modules) of coexpressed genes that then were examined for relationships with bone geometry and density. One module exhibited significant correlation with femur length (r = 0.416), anteroposterior diameter (r = 0.418), mediolateral diameter (r = 0.576), and bone mineral density (r = 0.475). Highly connected genes (n = 28) from this and other modules were tested in vitro using prechondrocyte ATDC5 cells and RNA interference. Five of the 28 genes were found to play a role in chondrocyte differentiation. Two of these, Hspd1 and Cdkn1a, were known previously to function in chondrocyte development, whereas the other three, Bhlhb9, Cugbp1, and Spcs3, are novel genes. Our integrative analysis provided a systems-level view of cartilage development and identified genes that may be involved in bone development. © 2011 American Society for Bone and Mineral Research.
Highlights
Mesenchymal cell condensation is the starting point of skeletal patterning, outlining the shapes of future bones.[1]
We used a systems-based approach to identify candidate pathways and genes involved in chondrocyte differentiation
Five genes were shown to influence chondrocyte differentiation significantly, as judged by siRNA knockdown, two of which have been implicated in bone biology in previous studies
Summary
Mesenchymal cell condensation is the starting point of skeletal patterning, outlining the shapes of future bones.[1]. The mesodermal cells subsequently differentiate into chondrocytes to form the templates of the long bones. Chondrocytes in the growth plates of long bones undergo a coordinated differentiation process. They begin to proliferate, hypertrophy, and undergo terminal differentiation. Chondrocyte differentiation is a multistep process characterized by successive changes in cell morphology and gene expression. This multistep process requires the coordinated expression of many genes, including genes encoding proteins for extracellular matrix (ECM), morphogenesis, proliferation, angiogenesis, and apoptosis.[5,6] Disturbances of these processes can lead to skeletal dysplasias.[6,7]
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