Researchers here review what is known of mechanisms contributing to the death of chondrocyte cells in aged joint cartilage. The loss of cartilage is characteristic of osteoarthritis, and given the prevalence of this condition in old people, there is considerable interest in finding ways to halt this process. Like all things in the biology of aging, it is far from simple and far from completely mapped, however. This paper omits mention of the likely role of cellular senescence in the development of osteoarthritis, something that seems much more relevant now that means of removing senescent cells are emerging, so you might treat this publication as a companion piece to another paper on that topic published earlier in the year.
Osteoarthritis (OA) is the most common chronic joint disease. OA pathophysiology was, for a long time, attributed to biomechanical constraints exerted on weight-bearing articulations (e.g., knees, hips). However, metabolic factors are also well recognized as mediators in the onset of OA. Adipose tissue can act as an endocrine organ, releasing bioactive molecules, such as pro-inflammatory cytokines, of which levels can be significantly and positively correlated with cartilage degradation in OA patients. OA is characterized by a progressive breakdown of articular cartilage, involving the remodeling of all joint tissues (bone, synovium, ligaments) with the appearance of osteophytes, synovial inflammation, subchondral bone thickening, and in fine joint space narrowing. Cartilage degradation constitutes one of the prominent hallmarks of the disease.
Articular cartilage is a conjunctive tissue composed of only one cell type, chondrocytes, enclosed in a self-synthesized extracellular matrix (ECM). These specific cells represent approximately 1% of total cartilage volume and are responsible for matrix composition and integrity, thereby conferring to cartilage its functions of mechanical support and joint lubrication. Histochemistry analyses have demonstrated the formation of chondrocytes clusters, the presence of irregular surfaces, cartilage volume loss, and matrix calcification in OA cartilage compared to normal cartilage. These changes in cartilage structure are linked to the alteration of molecular components of ECM. Distribution of the collagen II network is modified, being uniformly distributed throughout the normal cartilage layers, but at a decreased level in OA-degenerated areas and at an increased level in chondrocytes clusters.
Chondrocytes are quiescent cells that rarely divide under physiological conditions: Adult human cartilage is a post-mitotic tissue displaying virtually no cellular turnover. Moreover, the ECM is not innerved nor vascularizated, thereby avoiding new cell supply to compensate for potential cellular loss. As a consequence, phenotypic stability, anabolic/catabolic balance activity, and survival of chondrocytes are crucial for the maintenance of proper articular cartilage. During the course of OA, all of these criteria are modified. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Although an excess of autophagy can lead to cell death, the current view is that the trigger of autophagy in chondrocytes aims to avoid cell death, especially in the early stages of OA.
Currently, there is no treatment for a full stop of OA progression. Therefore, preventing, limiting, or delaying chondrocyte cell death, in order to maintain cartilage matrix integrity, might constitute a tempting approach. Caspase inhibitors are the most studied among all of the apoptosis regulators in OA. However, a tight control of the delivery site of these anti-apoptotic agent should be required (limited to the cartilage injury site) in order to avoid the risk of systemic malignancies. In addition, studies have shown that chondrocytes shifted towards necrotic cell death, suggesting that cells trying to avoid apoptosis paved the way for another dying process, such as necrosis. Minimizing oxidative stress and preserving mitochondria integrity could constitute an alternative approach. Antioxidants have demonstrated anti-apoptotic and anti-OA effects in rat and mouse models. Promoting autophagy could also indirectly act on removing defective mitochondria and the associated oxidative stress. Moreover, as key autophagic proteins were found to be decreased in aging and OA cartilage, restoring autophagy could be considered to delay OA development. A better molecular delineation of apoptotic and autophagic processes may help in designing new therapeutic options for OA treatment.