Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix

Abstract

Objective: Age-related changes in multiple components of the musculoskeletal system may contribute to the well established link between aging and osteoarthritis (OA). This review focused on potential mechanisms by which age-related changes in the articular cartilage could contribute to the development of OA.

Methods: The peer-reviewed literature published prior to February 2009 in the PubMed database was searched using pre-defined search criteria. Articles, selected for their relevance to aging and articular chondrocytes or cartilage, were summarized.

Results: Articular chondrocytes exhibit an age-related decline in proliferative and synthetic capacity while maintaining the ability to produce pro-inflammatory mediators and matrix degrading enzymes. These findings are characteristic of the senescent secretory phenotype and are most likely a consequence of extrinsic stress-induced senescence driven by oxidative stress rather than intrinsic replicative senescence. Extracellular matrix changes with aging also contribute to the propensity to develop OA and include the accumulation of proteins modified by non-enzymatic glycation.

Conclusion: The effects of aging on chondrocytes and their matrix result in a tissue that is less able to maintain homeostasis when stressed, resulting in breakdown and loss of the articular cartilage, a hallmark of OA. A better understanding of the basic mechanisms underlying senescence and how the process may be modified could provide novel ways to slow the development of OA.

Fig. 1. Cell senescence

There are two major types of cell senescence-replicative (intrinsic) and stress-induced (extrinsic). Senescence is associated with telomere dysfunction, formation of senescence-associated (SA) heterochromatin, and increased expression of p53, p21, and p16. The senescent secretory phenotype is characterized by increased production of cytokines, matrix metalloproteinases (MMPs) and growth factors such as epidermal growth factor (EGF) or growth factor binding proteins such as insulin-like growth factor binding protein-7 (IGFBP-7).

Fig. 2. Theoretical model for the relationships of aging, oxidative stress, and the development of osteoarthritis

Aging-related oxidative stress as well as abnormal biomechanical stress results in increased levels of reactive oxygen species (ROS) in chondrocytes. The increase in ROS modulates anabolic and catabolic signaling pathways resulting in reduced matrix synthesis, inhibition of growth factor expression, and increased production of matrix metalloproteinases (MMPs) and cytokines that lead to matrix loss and osteoarthritis. Aging also results in increased formation of advanced glycation end-products (AGEs) which causes increased fatigue failure of the cartilage that when stressed also contributes to the development of osteoarthritis.