Identification and validation of therapeutic targets in osteoarthritis and diabetes-associated osteoarthritisRole of autophagy

Abstract

Defects in homeostatic mechanisms, such as autophagy, contribute to joint aging and precede joint damage in osteoarthritis (OA). Furthermore, these defects could be pathological mechanisms in comorbidities associated with OA, such as type 2 diabetes (T2D). Therefore, the objective of this Doctoral Thesis focused on identifying autophagy markers involved in joint damage associated with osteoarthritis and osteoarthritis associated with T2D (OA-T2D). To address this objective, we analyzed an autophagy gene expression array using blood from subjects without osteoarthritis and subjects with knee OA from the Prospective Cohort of OA of A Coruña (PROCOAC). A total of 16 autophagy-related genes were found to be decreased in patients with knee OA. Through validation studies, we observed that the expression of HSP90AA1, a relevant marker in chaperone-mediated autophagy (CMA) and involved in protein folding and in the response to stress, was decreased in blood and joint tissues of subjects with knee OA. Functional studies in chondrocytes from subjects with OA indicated that HSP90AA1 plays an important role in chondrocyte homeostasis by regulating the connection between the CMA and the macroautophagy. In fact, the HSP90AA1 defect in OA chondrocytes was related to a decrease in CMA and macroautophagy and, as a consequence, to an increase in inflammation, oxidative stress and senescence that ultimately lead to the death of the chondrocyte by apoptosis, while HSP90AA1 overexpression protected against joint damage. On the other hand, we confirm that HSP90AA1 is more decreased in kee OA-T2D subjects compared to knee OA subjects. In conclusion, we propose that HSP90A is key to maintain chondrocyte homeostasis by regulating CMA and macroautophagy, whereas a CMA defect contributes to joint damage. These results suggest that CMA is a key homeostasis mechanism for joint health and its activation could have therapeutic effect against joint damage and the progression of OA and their comorbidities.