Origins of bone and cartilage disease. (360G-Wellcome-101123_B_13_A)

In a pilot study of 100 knockout mouse lines we developed a rapid-throughput skeletal phenotyping platform and identified nine new genes with diverse, unrelated and unpredictable functions that determine bone mass and strength. We hypothesise that large-scale phenotyping of knockout mice will identify novel susceptibility alleles for bone and joint disorders and genes that underpin skeletal physiology. Thus, we will extend our platform to identify phenotypes affecting cortical and trabecular b one structure and strength in female mice from 1160 knockout lines generated by the Wellcome Trust Sanger Institute (WTSI) Mouse Genetics Project. In parallel, we will validate a rapid-throughput screen to identify abnormalities of joint morphology, articular cartilage integrity and subchondral bone mineralisation in male mice. Comprehensive studies in selected mutants will incorporate (i) disease-provocation models to determine whether gene deletions affect the onset or progression of bone lo ss and cartilage destruction, and (ii) transcriptome analyses to identify gene networks that control skeletal development, maintenance, and function. Collaborations with international consortia studying bone density, fracture and osteoarthritis in human populations will translate gene identification to human disease. Rapid dissemination of annotated data will be achieved through the WTSI and a new Origins of Bone and Cartilage Disease website.