The extracellular matrix (ECM) is a complex network of proteins and glycosaminoglycans, which constitute several tissues of multicellular organisms. ECM is a three-dimensional scaffold that defines tissue boundaries, biomechanical properties, cell polarity and provides biochemical signals that control cell survival, proliferation and differentiation. ECM remodeling is essential during a number of physiological processes, the dysregulation of the remodeling causes musculoskeletal, cardio-vascular, skin, ocular and renal diseases.
Skin disorders as well as skin aging are caused by an inappropriate ratio between Collagen type I and type III and a abnormal structure and localization of polysaccarides and proteoglycans. These alterations can lead to skin atrophy and skin cancer, such as melanoma. Also osteoarthritis, the most common rheumatic disease, affecting cartilage, is characterized by an imbalance between synthesis and degradation of the ECM components. All these pathologies are non-curable diseases, therefore to find molecules that can stimulate ECM synthesis and block tissue degradation is the current challenge. Previously, we studied glucosamine and glucosamine-derivatives, finding that these molecules are able to counteract inflammation, which is present during the onset and progression of ECM impairment and are also able to stimulate ECM component synthesis.
Aim of the present project is to further study the glucosamine-derivatives, which has been extensively studied on chondrocytes, and now we want to study these molecules on dermal fibroblasts. Moreover, we are going to study new glucosamine-derivatives in order to find molecules that can be used at lower concentration compared to the concentration used for the previous compounds. Very interestingly, the glucosamine is safe when administered to patients, also at very high dosage, without undesired side effect, therefore we can suppose that also its derivatives would be safe.
The innovation of the project is to find molecules that can ameliorate the treatments of pathologies, which nowdays are not curable, such as skin disorders and osteoarthritis (OA), as well as molecules that can be used to treat the impairments of the skin photoaging.
Skin disorders and osteoarthritis are caused by impairments of extracellular matrix (ECM), which is the main component of connective tissues.
Regarding skin disorders, very common is the photoaging, induced by UVB irradiation of the skin. Fibroblasts and keratinocytes are involved, their alterations can lead to development of skin atrophy or skin cancer. To date, both skin atrophy and skin cancer have not a resolving cure. Particularly, malignant tumors can progress to an aggressive metastatic disorder commonly resistant to immunochemotherapy. Thus there is an urgent need to improve the therapeutic options.
Regarding the osteoarthritis, it is the main rheumatic disease, involving the cartilage, another connective tissue consisting of an abundant ECM. OA induces extensive articular damage, causing pain and disability in patients with negative relapse on the life¿s quality of patients as well as on social sanitary costs mostly in industrialized countries. OA is a non-curable disease and its pharmacological treatment is based mainly on analgesic agents or non-steroidal anti-inflammatory drugs. Structure-modifying agents, such as glucosamine (GlcN), condroitin sulfate, diacerein and curcumin are also administered to OA patients, but effectiveness is not definitively accepted. Current challenge is to find molecules able to block OA progression.
The molecules, topic of this project, were found able to counteract inflammatory pathways and induce ECM synthesis both in vitro in some cell types and in vivo in rabbit and mouse OA models. Moreover, these molecules should be safe, without side effects, if administered to patients, due to their chemical composition. They are composed by glucosamine, a natural amino sugar, coupled to amino acids, therefore, cells have the enzymes indispensable to metabolize these molecules.
To study these molecules in more details and in new cellular models and at same time to find new bioactive molecules, would be very promising approach to find new therapeutic strategies for non curable diseases.