[en] Osteoarthritis (OA) is the most common joint disease, affecting 70% of people over 65 years old. This disease is characterized by a gradual loss articular cartilage integrity, subcondral bone sclerosis and a variable grade of synovial inflammation. Currently, it is known that inflammation plays an important role in the disease progresion, and interleukin 1b (IL-1b) and tumoral necrosis factor a (TNF-a) are considered the main cytokines involved in this pathology. An increasing number of in vitro and in vivo studies have demostrated that osteoarthritic human chondrocytes present an altered mitochondrial function. This mitochondrial dysfunction may affect several pathways that have been implicated in cartilage degradation, including defective chondrocyte biosynthesis and growth responses, increased condrocyte apoptosis and matrix calcification; as well as an increment in destructive and inflammatory response. In relation to synovial tissue, an asociation between mitochondrial mutagenesis and inflammatory response has been described in inflammatory arthritis. Furthermore, diverse pro-inflamatory mediators found in the osteoarthritic condition, such as IL-1b and TNF-a, could alter mitochondrial function in the condrocyte and synoviocyte. Therefore, the role of the mitochodrion and inflammatory pathways in the pathogenesis of OA is evident. In this study, we demonstrate for the first time that mitochondrial dysfunction amplifies the inflammatory response induced by cytokines in human normal chondrocytes in vitro, supporting the hypothesis that damage in mitochondrial function could actively participate in the inflammatory phenotype observed in the osteoarthitic chondrocyte. This effect is mediated, at least partially, by an increase in oxidative stress, activation of the nuclear factor NF-kB and caspase activation. Furthermore, resveratrol, an anti-oxidant and anti-inflammatory molecule, found in certain foods such as black grapes and derivatives, is able to reduce the catabolic response induced by the synergy between mitochondrial dysfunction and cytokines. This finding confirms resveratrol as a hopeful molecule in preventive and therapeutical treatments in OA. Finally, in this thesis an in vivo murine model of articular mitochondrial damage was also developed, showing that mitochondrial dysfunction in articular tissues may trigger the joint destruction by increasing the inflammatory response.

[gl] A artrose (OA) é a patoloxía articular mais frecuente na poboación, afectando a máis do 70% dos maiores de 65 anos. Esta enfermidade caracterízase pola degradación progresiva da cartilaxe articular hialina, engrosamento do óso subcondral e un grado variable de inflamación sinovial. Actualmente hai un consenso xeral que sinala á inflamación como factor clave na sua progresión, sendo as citoquinas interleuquina 1b (IL-1b) e o factor de necrose tumoral a (TNF-a) dous dos principiais mediadores implicados nesta patoloxía. Diversos estudos ex vivo e in vitro demostraron que os condrocitos humanos artrósicos teñen alterada a función mitocondrial. Esta disfunción mitocondrial pode afectar a varias das vías patolóxicas que median a degradación da cartilaxe, destacando a resposta defectuosa do condrocito ó crecemento e á biosíntese da matriz, o incremento da apoptose no condrocito e a calcificación da matriz da cartilaxe; así como un incremento da resposta inflamatoria e destructiva. En relación ó tecido sinovial, existe unha asociación entre a mutaxénese mitocondrial e a resposta inflamatoria na artrite inflamatoria. Ademais, observouse que diversos mediadores inflamatorios presentes no tecido artrósico, coma IL-1b e TNF-a, poden alterar a función mitocondrial tanto no condrocito coma no sinoviocito. Por todo iso, a importancia da mitocondria e a resposta inflamatoria no desenvolvemento da OA é evidente. Neste traballo, demóstrase por primeira vez que a disfunción mitocondrial amplifica a resposta inflamatoria inducida por citoquinas en condrocitos humanos normais in vitro, reforzando a hipótese de que un dano na función mitocondrial pode participar activamente no fenotipo inflamatorio observado no condrocito artrósico. Este efecto é mediado, polo menos en parte, por un incremento do estrés oxidativo e da activación do factor nuclear NF-kB, así coma da activación das caspasas. Ademais, o resveratrol, unha molécula anti-oxidante e anti-inflamatoria, presente nalguns alimentos como as uvas e derivados, é capaz de reducir a resposta catabólica inducida pola sinerxia entre a disfunción mitocondrial e as citoquinas; consolidándose como unha molécula prometedora para fins terapéuticos e preventivos na OA. Finalmente, neste estudo desenvólvese in vivo un modelo articular murino de dano mitocondrial, demostrándose que a disfunción mitocondrial nos tecidos articulares pode provocar a destrucción articular, ó incrementar a resposta inflamatoria.