Implication et caracterisation du metabolisme anormal des osteoblastes arthrosiques humains de l'os sous-chondral dans le developpement de l'arthrose (French text)

Osteoarthrosis (OA) is a disease characterized by a progressive loss of articular cartilage accompanied by subchondral bone sclerosis. To day, the aetiology of this disease still remains unknown. However, recent data have suggested an active participation of bone in the initiation and/or progression of this disease, which could greatly alter our approach in its treatment. Our hypothesis is that a phenotypical alteration of OA osteoblasts (Ob) could be responsible for the initiation and/or progression of OA resulting from an abnormal bone metabolism. To evaluate this hypothesis, we have developed a primary cell culture model of Ob isolated from the human subchondral bone plate of tibial plateau. Our results have demonstrated that OA Ob are more resistant than normal Ob to PTH stimulation, which is the principal bone resorbing hormone, thus partially explaining the bone sclerosis observed in OA. On the other hand, OA Ob presents an increased metabolism, characterized by their high level of alkaline phosphatase activity and osteocalcin release. Moreover, the principal bone anabolic factors, namely TGF-β and IGF-1, are also increased in OA Ob, which could further enhance bone sclerosis. Experiments were also conducted to clearly evaluate the production of a variety of bone factors by OA Ob. Our results indicated that IL-6 and PGE₂ production by subchondral Ob can discriminate two subgroups of OA patients that cannot otherwise be separated by their phenotypic cell markers. Those subgroups, possibly representing different stages in this pathology, have allowed us to explain a variety of characteristics of OA Ob, such as their increased IGF-1 and LTB₄ production. Finally, we also demonstrated a downregulation of the IGF-1 binding proteins and some alterations in the signal transduction of IGF-1 in OA Ob, which clearly demonstrate an abnormal bone metabolism by these cells. Indeed, OA Ob presented an increased activation of the MAPK pathway following IGF-1 stimulation, thus giving an insight to the molecular mechanisms involved in their upregulation. The aim of our study was to demonstrate the importance of the subchondral bone in OA in order to promote clinical interventions that are considering every component of the articulation, compared to the current cartilage-oriented interventions.