This proposal is focused on translation control in cartilage biology. Chondrocytes are the primary cells responsible for the growth and maintenance of bones and cartilage tissue. Deregulation of chondrocyte homeostasis gives rise to a variety of musculoskeletal disorders, including osteoarthritis (OA). While many studies have focused on transcriptional mechanisms involved in regulation of chondrocytes proliferation and differentiation, the role of translation control in these processes has never been addressed. It is well established, that chondrocytes proliferation and differentiation are regulated by a number of signaling molecules and one of the central roles in these processes belongs to Fibroblast Growth Factors (FGFs). While in most cell types FGFs induce proliferation and protect from apoptosis, proliferating chondrocytes are distinct in their response to FGF, responding with growth inhibition. According to our preliminary data, protein synthesis is dramatically decreased in FGF-treated chondrocytes, a response that is opposite to well established stimulation of protein synthesis by growth factors in many other systems. Moreover, we were able to detect FGF-induced activation of eukaryotic Initiation Factor 4E Binding Protein (4E-BP) which is a known inhibitor of cap-dependent translation. While 4E-BP was also active in human articular chondrocytes, its activity was significantly lower in OA cartilage, indicating deregulation of translational apparatus under this pathological condition. This proposal aims to investigate the mechanism that mediates FGF-induced downregulation of protein synthesis in proliferating chondrocytes and regulation of protein synthesis during differentiation of chondrocytes. In the first part of this application we will investigate FGF-induced inhibition of protein synthesis in proliferative chondrocytes. We will determine the mechanism leading to this diverse response. The second part of our proposal will aim to identify specific pools of mRNAs that are actively translated under general repression of protein synthesis. We will employ ribosomal profiling to identify these mRNAs. The last part of the proposal will aim to determine the mechanism leading to activation of translation machinery in OA cartilage when compared to normal human cartilage. This project will provide basis for facilitating new specific targets in OA and other musculoskeletal disorders.
The proposal aims to investigate the mechanisms of translation control in growth plate and articular chondrocytes. We will try to understand the molecular basis of dysregulation of protein synthesis in osteoarthritis cartilage. This study will e important for designing novel therapeutic strategies for the treatment of osteoarthritis.
|Katsara, Olga; Attur, Mukundan; Ruoff, Rachel et al. (2016) Increased activity of chondrocyte translational apparatus accompanies osteoarthritis. Arthritis Rheumatol :|
|Ruoff, Rachel; Katsara, Olga; Kolupaeva, Victoria (2016) Cell type-specific control of protein synthesis and proliferation by FGF-dependent signaling to the translation repressor 4E-BP. Proc Natl Acad Sci U S A 113:7545-50|