Molecular Pathways Regulating Skeletal Development and Osteoarthritis Pathogenesis
Our lab is working on the biology of the mammalian skeleton as well as bone and joint diseases, most notable osteoarthritis. Osteoarthritis is a common, debilitating and expensive disease, affecting approximately 4 million Canadians directly. Despite this staggering number, no treatments to slow, stop or reverse the disease itself are available. One reason for this lack of disease-modifying treatments is our poor understanding of the mechanisms that start and drive osteoarthritis. Our main interest is to identify and study these mechanisms, with the long term aim of identifying new treatments for this disease.
In the second approach we use unbiased, genome-wide studies to identify novel pathways affected in our mouse and rat models of osteoarthritis. We have published extensively on Affymetrix microarray studies and recently incorporated Next Generation Sequencing approaches (ChIP Seq, RNA Seq) into our repertoire. Through these approaches we have identified several novel pathways involved in osteoarthritis pathogenesis that we are now studying in depth. Examples of such pathways include the TGFalpha-EGFR pathway and a number of nuclear receptors. These manuscripts provide some examples of our recent studies on these pathways: http://www.ncbi.nlm.nih.gov/pubmed/25331977, http://www.ncbi.nlm.nih.gov/pubmed/24966136.
In both approaches, our major focus is on functional examination of identified genes using conditional mouse mutagenesis, using a number of tissue-specific and/or tamoxifen-inducible Cre driver lines (as in the publications listed above). Conditional KO mice are being investigated both during skeletal development and in several models of osteoarthritis established in the lab, including surgical and aging models. We employ a large number of outcome measures, such as molecular and histological examination, microCT imaging and behavioral assays. In some cases, we have proceeded to test pharmacological inhibitors of key pathways in our rat models of osteoarthritis, with promising results. These studies should ultimately pave the way for studies in large animal models, a key step in translating our findings to applications in human patients. The described in vivo approaches are accompanied by many in vitro studies using cell and organ culture and a multitude of molecular and cellular assays.
Through our studies we have already provided many important insights into cartilage and joint biology throughout development, aging and disease. Many more exciting projects are under way, so stay tuned!