Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

Abstract

Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA.

Keywords: OA; aging; autophagy; cartilage; chondrocytes; inflammation; senescence; therapeutics.

Figure 1

Hypothetical mechanisms underlying the putative role of the circadian rhythm and energy sensors in the inflammation-associated phenotype switch of chondrocytes in osteoarthritis: from molecular actors to therapeutic potential interventions.

Figure 2

Schematic diagram illustrating the interrelation between autophagy, senescence and inflammation in the onset of osteoarthritis (OA). During aging, after trauma or stress associated with to decreased autophagy and increased oxidative stress, chondrocytes become senescent and secrete a Senescence-Associated Secretory Phenotype (SASP). Factors secreted in the SASP propagate senescence and inflammation to surrounding cells and tissues through a paracrine process and participate to OA. Moreover, the cartilage degradation products called damage associated molecular patterns (DAMP) reinforce inflammation and senescence notably via an increase in oxidative stress (ROS). ROS, Reactive oxygen Species; SIRT, Sirtuin; SASP, senescence associated secretory phenotype; NF-kB, nuclear factor-kappa B; cGAS, Cyclic GMP-AMP synthase; STING, stimulator of interferon genes; TLR, Toll-like Receptor; RAGE, Receptor for Advanced-Glycation End Products; HMGB-1, High Mobility group Box-1; IL-1, interleukin-1; TNF, tumor necrosis factor; IL6, interleukin 6; IL8, interleukin 8; DAMP, Damage-Associated molecular pattern.