The role of autophagy in mitigating osteoarthritis progression via regulation of chondrocyte apoptosis: A review.

Osteoarthritis (OA) is the most prevalent chronic joint disease with an immense socioeconomic burden; however, no treatment has achieved complete success in effectively halting or reversing cartilage degradation, which is the central pathophysiological feature of OA. Chondrocytes loss or dysfunction is a significant contributing factor to the progressive cartilage deterioration as these sole resident cells have a crucial role to produce extracellular matrix proteins, thus maintaining cartilage structure and homeostasis. It has been previously suggested that death of chondrocytes occurring through apoptosis substantially contributes to cartilage degeneration. Although the occurrence of apoptosis in osteoarthritic cartilage and its correlation with cartilage degradation is evident, the causes of chondrocyte apoptosis leading to matrix loss are still not well-understood. Autophagy, an intracellular degradative mechanism that eliminates dysfunctional cytoplasmic components to aid cell survival in unfavourable conditions, is a potential therapeutic target to inhibit chondrocyte apoptosis and reduce OA severity. Despite accumulating evidence indicating significant cytoprotective effects of autophagy against chondrocyte apoptosis, the mechanistic link between autophagy and apoptosis in chondrocytes remains to be further explored. In this review, we summarize the relevant mechanistic events that perpetuate chondrocyte apoptosis and highlight the prominent role of autophagy in modulating these events to mitigate OA progression.

The potential mechanism of hypoxia-induced tenogenic differentiation of mesenchymal stem cell for tendon regeneration.

Tendon injuries account up to 50% of all musculoskeletal problems and remains a challenge to treat owing to the poor intrinsic reparative ability of tendon tissues. The natural course of tendon healing is very slow and often leads to fibrosis and disorganized tissues with inferior biomechanical properties. Mesenchymal stem cells (MSC) therapy is a promising alternative strategy to augment tendon repair due to its proliferative and multilineage differentiation potential. Hypoxic conditioning of MSC have been shown to enhance their tenogenic differentiation capacity. However, the mechanistic pathway by which this is achieved is yet to be fully defined. A key factor involved in this pathway is hypoxia-inducible factor-1-alpha (HIF-1α). This review aims to discuss the principal mechanism underlying the enhancement of MSC tenogenic differentiation by hypoxic conditioning, particularly the central role of HIF-1α in mediating activation of tenogenic pathways in the MSC. We focus on the interaction between HIF-1α with fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta 1 (TGF-ß1) in regulating MSC tenogenic differentiation pathways in hypoxic conditions. Strategies to promote stabilization of HIF-1α either through direct manipulation of oxygen tension or the use of hypoxia mimicking agents are therefore beneficial in increasing the efficacy of MSC therapy for tendon repair.