Senescent cells are large. They do not replicate, that function is disabled, but it is as if they go to the effort of producing all the material needed for replication, and thus swell up in size. A lot of the distinctive behavior of senescent cells seems quite connected to the fact that they are large. Insofar as aging is concerned, the important aspects of senescent cells are (a) whether or not they are being cleared rapidly and efficiently enough to keep their numbers down, and (b) the inflammatory, damaging signals they secrete. As senescent cell numbers grow, they cause ever more dysfunction in the surrounding tissue and the body at large.
In today’s open access paper, researchers tie together observations of enlargement in the chondrocyte cells that make up cartilage tissue, that growth in size involved in the transformation of cartilage to bone, with the incidence of cellular senescence in those cells. Osteoarthritis, involving chronic inflammation and degeneration of cartilage, may be largely driven by cellular senescence. If examining large chondrocytes, there is no doubt some degree of overlap between dysfunction in which too much transformation to bone is taking place, versus rising levels of cellular senescence. But how much overlap?
Research into cellular senescence is at a peculiar stage at the moment. Senescent cells are clearly involved in near every age-related disease, but the research community at large has only become earnestly engaged in this topic over the last five years or so. There are a great many diseases of aging, and only so many scientists. So cellular senescence, despite being of great importance to the treatment of aging, is still poorly explored in the specific context of most conditions. Researchers are likely to learn more by deploying one of the proven senolytic drugs to destroy senescent cells than they are through analysis of the disease state without intervention – but again, many diseases and only so many research teams.
Osteoarthritis (OA) is the most common joint disorder throughout the whole human population. OA accompanies progressive degradation of the articular cartilage, which leads to a loss of joint mobility and function and eventually to a low quality of life in patients due to both pain and restricted lifestyles. Healthy chondrocytes usually display moderate metabolic activity and proliferation under normal conditions; however, some articular chondrocytes lose their differentiated phenotype under diseased conditions and enter an endochondral ossification (EO)-like state of proliferation along with abnormal hypertrophic differentiation. Cellular senescence can also occur alongside hypertrophy due to similar stimuli. Cellular senescence and hypertrophy share various markers and processes, and both events are reported to play a role in the development of OA.
Chondrocyte hypertrophy and cell death are natural phenomena that usually occur during a developmental process called EO. Hypertrophic chondrocytes appear and play a crucial role in EO. Hyaline cartilage can be divided into two groups, (1) temporary and (2) permanent cartilage. Healthy cartilage is usually called permanent cartilage or resting chondrocytes, which are present in the articulating joint. Usually, permanent cartilage has a low proliferation rate and does not undergo terminal differentiation and EO. Temporary cartilage is initially formed as cartilage, but the final product is bone. Chondrocytes undergo active proliferation and generate a cascade of cells; whereas some of them undergo enlargement, others undergo hypertrophical changes and become hypertrophic chondrocytes. These cells increase their volume dramatically and the surroundings become mineralized to develop bone tissue.
Although various cell types are involved in OA pathology, chondrocytes are primarily thought to play a major role in OA induction by cellular senescence. When senescent cells were transplanted into the knee joint of wild type mice, an OA-like state was induced, which included pain, impaired mobility, and morphological and histological changes. The senescence-associated secretory phenotype of senescent cells can alter the tissue microenvironment and impair tissue regeneration induced by stem cells or progenitor cells, which can eventually lead to the senescence of the neighboring cells. Beside chondrocytes, synovial fibroblasts are also thought to initiate or progress OA through senescence. Nuclear expression of p16 was detected in higher amounts in OA synovial tissue samples when compared to that of normal synovial tissues, which indicates senescence in OA synovial fibroblasts.
The molecular mechanisms of OA initiation and progression require considerable further study, despite significant progress in recent years. OA is mainly caused by trauma induced by an external force or cartilage damage accumulated during aging. During these processes, chondrocyte hypertrophy and senescence are thought to play a critical role in OA initiation or progression. However, the remaining question is: which came first, the chicken or the egg? There is still little understanding of whether these two independent processes (i.e., chondrocyte hypertrophy and senescence) are dependent on penetration in the other. Further study on which event is the cause or the effect should be conducted to better understand these processes.