The role of autophagy in aging-related osteoarthritis
- Francisco J. Blanco García Co-director
- Beatriz Caramés Co-director
Universidade de defensa: Universidade da Coruña
Fecha de defensa: 05 de decembro de 2017
- Manuel Collado Rodríguez Presidente
- María del Carmen Arufe Gonda Secretaria
- María del Carmen de Andrés González Vogal
Tipo: Tese
Resumo
A common feature in pathologies related to aging is the progressive accumulation of damaged macromolecules that cause cellular injury and finally death. Autophagy is a fundamental mechanism in cellular homeostasis that regulates the elimination of damaged molecules and performs a protective function and cell survival. Recent studies have indicated a decrease in autophagy in the cartilage and aged and osteoarthritic chondrocytes. On the other hand, there is clear evidence that mitochondrial dysfunction plays a key role in the acceleration of the aging process. In this sense, different lines of evidence have shown mitochondrial dysfunction in osteoarthritis cartilage. Based on these premises, the objectives proposed in this Doctoral Thesis have been: (1) To study the effects of a defect of autophagy on mitochondrial function through pharmacological and genetic approaches and (2) Identify therapeutic targets associated with a decrease in autophagy in the pathology of the musculoskeletal system. To carry out these studies we use pharmacological and genetic approaches to inhibit autophagy and study this effect on mitochondrial function in human chondrocytes. In addition, we analysed the proteome of human chondrocytes associated with a decrease in autophagy for the identification of potential therapeutic targets. Finally, we validate the target identified using the genetic editing technology CRIPSPR/Cas9 in human chondrocytes and a model of genetic deletion in mouse. In conclusion, our data highlights the role of autophagy as a critical protective mechanism against joint damage; therefore, pharmacological interventions aimed at activating autophagy may have condroprotective activity against the degenerative processes of the musculoskeletal system.