Elucidating the molecular mechanisms underlying retinoid action in chondrogenesis

Musculoskeletal diseases represent the largest burden to the healthcare system and are major contributors to long-term disability and reduced quality of life. Degenerative joint diseases, such as osteoarthritis, make up the largest proportion of musculoskeletal diseases. Osteoarthritis is characterized by a deficiency of particular cartilage, which results in a loss of joint mobility, pain, deformity and dysfunction. The research being undertaken by Helen Dranse involves characterizing the basic mechanisms that regulate the formation of cartilage, or chondrogenesis, with a particular focus on the role of vitamin A and its metabolites, the retinoids. Retinoic acid (RA) plays an essential role in cartilage formation and related functions by regulating the expression of specific RA receptor (RAR) target genes. However, the mechanisms through which the RA signalling pathway influence chondrogenesis remain poorly understood. Recently, Ms. Dranse and colleagues identified a novel direct RAR target gene. The activation of RAR target genes is controlled to a large extent by RA availability, which is influenced by a number of factors including the CYP26 enzymes. In her current research, Ms. Dranse is examining the distribution of RA in the Cyp26b1-deficient mouse limb, and how this relates to the expression of genes involved in chondrogenesis and the newly identified and other potential RAR target genes. Having gained insight into these processes, Ms. Dranse will attempt to rescue the limb defects observed in Cyp26b1-deficient mice by eliminating the expression of the newly identified RAR target gene in these animals. The information generated from her work will provide much needed insights into the role of RAR-mediated signalling in the regulatory networks that underlie cartilage formation. A better understanding of the molecular processes that regulate chondrogenesis will consequently lead to novel therapeutic targets that enhance cartilage repair and/or regeneration in adults, and assist in the development of treatment strategies for degenerative joint disease.