Design of biosourced glycomimetics to stimulate cartilage regeneration in osteoarthritis – GAG-LIKE

Osteoarthritis (OA) is the most common joint disease, characterized by gradual loss of articular cartilage due to abnormal extracellular matrix (ECM) and changes in chondrocyte morphology and metabolism, associated to sub-endochondral bone remodeling and local synovitis. The burden of this disease has been gradually gaining importance in the last few decades with the aging of the population and the obesity epidemic. Beyond the huge healthcare costs for treatment of OA affecting 70 million individuals in Europe, there is no treatment that can repair the cartilage and stop the progress of OA. Existing therapies, based on Hyaluronic acid and Chondroitin sulfate injections, are symptomatic and pursue only pain alleviation with no effect on slowing disease progression and on restoring cartilage and chondrocytes functions. In parallel, new therapeutic strategies are currently based on stem cells, but these fragile cells are injected in an inflammatory microenvironment detrimental to their survival and clinical efficacy. Therefore, a more suitable middle is highly mandatory. GAGOSOME project is born from the observation that OA is closely related to a loss of proteoglycans (PGs), one of the largest component of the ECM. These PGs are not only structural components, but regulators of cell functions also since they interact with growth factors, cytokines, proteinases, adhesion receptors and extracellular matrix components through their sulfated glycosaminoglycan (GAGs) chains. As a consequence, these polysaccharides are new important classes of molecular targets in the fields of biochemistry, pathology and pharmacology. However, due to the natural extractive source of PGs and GAGs and their inherent complexity in terms of relative molecular mass, charge density, sulfation patterns, the relationship with functions are difficult to elucidate and their therapeutic and commercial use is complicated according to their poorly defined structures. Use of well-defined biomimetic structures are therefore the valuable alternatives for therapeutic strategies.
Attemps have relied on the idea that a limited number of sulfate groups on a smaller oligosaccharide scaffold may overcome the difficulties of working with GAGs or PGs. Examples of these include GAG related polysaccharides of non-mammal origin that have shown to stimulate healing of tissues. And, very recently, glycopolymers with oligomers of GAGs as side chains revealed fascinating ability to recapitulate biological features of natural PGs. Even for these short GAGs, their syntheses still pose significant challenges. These shortcomings can be remedied, through the GAG-LIKE project, by designing readily accessible GAG oligosaccharide mimetics with size-homogeneous and enabling controlled sulfation pattern. Additionally, as for native PGs, multi-presentation of GAG mimetics on a polymeric backbone will be achieved. Up to date, these approaches have never been investigated, especially in order to promote the articular cartilage homeostasis.
The GAG-LIKE project aims to develop PGs-like biopolymers made of architecturally defined grafted polyesters having sulfonates functional groups or simplified sulfated GAG mimetics. These glycomimetics will be assessed for their abilities to potentiate functional properties of mesenchymal stem cells and chondrocytes with applications in cartilage repair. The panel of biomimetic structures would greatly facilitated the fundamental explorations into the importance of macromolecular structure (e.g., sulfation pattern, density, distance, molecular weight and multivalency) and relationships with physicochemical properties in solution and with biological activities. Forces aligned within this consortium will combine crucial expertise in chemo-enzymatic modification of oligosaccharides (CERMAV-Grenoble), in the preparation of functional polyesters (ICMPE-Paris Est), and in the study of GAGs on the mesenchymal stem cells properties (CRRET-Paris Est & IBS-Grenoble).