Kennedy Trust Prize Studentships
Modulating retinoic acid signaling to treat hand osteoarthritis
Background and preliminary data
Hand osteoarthritis (OA) is a highly prevalent, debilitating condition that predominantly affects women around the time of the menopause. Pathogenesis of this condition is poorly understood but some recent insight has come from a genome wide association study (GWAS). In this study, based in an Icelandic population, hypomorphic variants in the gene ALDH1A2 were found to be associated with increased risk of diseases1. This gene encodes retinaldehyde dehydrogenase, a key enzyme in the synthesis of intracellular retinoic acid (RA). It was not associated with increased OA in knee or hip.
Retinoic acid production and signaling is complex, with different cellular responses determined by which cellular RA binding protein is selected and by which RA receptors are utilized2.
We examined genes regulated in response to cartilage injury (a primary risk factor for OA development) by microarray and RT-PCR. We found strong regulation of several genes on the RA pathway (unpublished and3,4). These included up-regulation of enzymes promoting RA synthesis (e.g. retinol dehydrogenase 12) as well as suppression of its key breakdown enzymes, Cyp26 a, b and c. Injury also leads to the up and down-regulation of a number of homeobox (Hox) target genes.
The aims of this project are to:
- Explore how mechanical injury drives retinoic acid pathways in cartilage.
- Define the specific RA pathways that are induced by injury and compare this response to activation by available RA agonists.
- Verify whether these genes are regulated in tissues from patients with hand OA.
RT-PCR; microarray analysis; cartilage injury assays; in vivo cartilage injury (OA model and focal cartilage defect model); handling human diseased and normal tissue; design of clinical experimental medicine trial.
Vincent: Director of OA Pathogenesis Centre. Currently has 3 students, 2 post docs and 1 technician working in her team. She also manages another 4 technicians associated with the OA Centre (most of whom are post-doctoral scientists). The group works closely with other PIs within the OA Centre including 2 hand surgeons (Gardiner and Furniss).
- Styrkarsdottir, U. et al. Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nat. Genet. 46, 498–502 (2014).
- Cunningham, T. J. & Duester, G. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nature Publishing Group 16, 110–123 (2015).
- Vincent, T., Hermansson, M., Bolton, M., Wait, R. & Saklatvala, J. Basic FGF mediates an immediate response of articular cartilage to mechanical injury. Proc. Natl. Acad. Sci. U.S.A. 99, 8259–8264 (2002).
- Burleigh, A. et al. Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo. Arthritis Rheum. 64, 2278–2288 (2012). .
Infection & Immunity
The admissions process open in late October.