Chondrocytes are the cartilage primary cells responsible for the pattering and growth of much of the skeleton, particularly the long bones and cartilage tissue. Formation and remodeling of cartilage requires efficient synthesis of extracellular matrix proteins and equally efficient expression of matrix-degrading enzymes. Imbalanced chondrocyte homeostasis leads to a variety of musculoskeletal disorders from cartilage degeneration in the joint in osteoarthritis (OA) to inadequate chondrocyte proliferation in the growth plate in achondroplasia. Our recent work revealed that regulation of mRNA translation plays a crucial role in chondrocyte homeostasis, as we demonstrated the importance of 4E-BP (eukaryotic initiation factor (eIF) 4E Binding Protein, a repressor of cap-dependent translation) in FGF-induced growth arrest in proliferating chondrocytes as well as in sustaining healthy articular cartilage. By binding to the critical translation initiation factor eIF4E, which is required to recognize the cap structure of eukaryotic mRNA and assemble a multi- subunit complex called eIF4F that recruits the 40S ribosome, 4E-BP functions to repress translation of select capped mRNAs that are eIF4F-dependent. In the first part of this application we will elucidate the mechanism of FGF-induced 4E-BP activation in chondrocytes. To understand further the complex post-transcriptional gene control upon FGF signaling in chondrocytes we plan to determine a role of Patl1 (Protein PAT1 homolog 1) ? a protein involved in mRNA stability. We identified this protein in our phosphoproteomics analysis as FGF responsive and necessary for mediating FGF inhibitory response. We will investigate the mechanisms that govern translation control during chondrocyte differentiation focusing on the proper balance between osteo- adipo- and chondrogenesis. In the last part of our application chondrocytes we will investigate how dysregylation of eIF4F impacts global mRNA translation profile of OA cartilage and investigate if modulation of the eIF4F activity can reverse OA like phenotype in vitro and in vivo.
The goal of this project is to determine the mechanisms of post-transcriptional control in a growth plate and in articular chondrocytes. The proposal aims to examine drugs that target components of translational apparatus and consequently specific mRNAs in OA cartilage to reduce cartilage degeneration. This study will be important for designing novel therapeutic strategies for slowing or stopping the progression of osteoarthritis.
