Featured Article: Deficiency of G-protein coupled receptor 40, a lipid-activated receptor,heightens in?vitro- and in?vivo-induced murine osteoarthritis

Osteoarthritis (OA) is an age-related degenerative joint disease. To date, its management is focused on symptoms (pain and inflammation). Studies suggest that fatty acids can reduce the expression of inflammatory and catalytic mediators, and improve in vivo joint function. Free fatty acid receptors (FFARs) such as G-protein coupled receptor 40 (GPR40) are proposed as attractive therapeutic targets to counteract inflammation and cartilage degradation observed in OA. This study aims to elucidate the involvement of GPR40 in OA. In this study, we used an in vitro model of OA, and surgically induced OA by ligament transection and partial meniscectomy in wild-type and GPR40 deficient mice. OA phenotype was investigated in vivo by histology and genes expression. We demonstrate that IL-1β-treated GPR40^−/− chondrocytes secret more inflammatory mediators (nitric oxide, interleukin-6, prostaglandin E2) and active catabolic enzymes (metalloproteinase-2, -9 [MMP-2, MMP-9]), and show decreased anabolism (glycoaminoglycan) compared to GPR40^+/+ cells. In accordance with these results, we show that GPR40^−/− mice exhibit an aggravated OA-induced phenotype characterized by higher tidemark exposure, frequency of osteophyte formation and subchondral bone sclerosis. Altogether our results demonstrate that GPR40 deficiency leads to an extended OA phenotype, providing evidence that increasing GPR40 activity, by natural or synthetic ligands, could be a new strategy in the management of OA.     

Crucial role of the Rcl1p–Bms1p interaction for yeast pre-ribosomal RNA processing

The essential Rcl1p and Bms1p proteins form a complex required for 40S ribosomal subunit maturation. Bms1p is a GTPase and Rcl1p has been proposed to catalyse the endonucleolytic cleavage at site A₂ separating the pre-40S and pre-60S maturation pathways. We determined the 2.0 Å crystal structure of Bms1p associated with Rcl1p. We demonstrate that Rcl1p nuclear import depends on Bms1p and that the two proteins are loaded into pre-ribosomes at a similar stage of the maturation pathway and remain present within pre-ribosomes after cleavage at A₂. Importantly, GTP binding to Bms1p is not required for the import in the nucleus nor for the incorporation of Rcl1p into pre-ribosomes, but is essential for early pre-rRNA processing. We propose that GTP binding to Bms1p and/or GTP hydrolysis may induce conformational rearrangements within the Bms1p-Rcl1p complex allowing the interaction of Rcl1p with its RNA substrate.     

Optimisation des matériaux hybrides à base de cellules souches pour la réparation de grands défauts osseux

The limitations imposed to both autogenous and allogenous bone grafts led to the development of new strategies for the treatment of large bone defects. The approach of bone tissue engineering aims to restore damaged bone tissue by combining osteocompetent cells such as mesenchymal stromal cells (MSC), and material scaffolds like ceramics. However, the therapeutic effectiveness of cell constructs has not yet met that of autologous bone grafts, in part due to the high death rate of cells (loaded onto the material scaffold) upon their implantation into the injured site. In order to improve the therapeutic functionality of these cell constructs, different strategies can be implemented. In this context, the Glassbone project aimed to optimize the conditions for preparation of tissue engineered products by approaching three aspects: identification of optimal ceramic scaffold relevant to bone formation; survival of implanted cells post-implantation, and finally cell preconditioning to promote cell viability in vivo. Such project will pave the way for the development of new “pro-survival” tissue engineered materials for optimal tissue regeneration.