Senescent cells cause harm throughout the body, accumulating in number with advancing age. They are found in all tissues, and this includes the cells of the immune system. The growing presence of senescent cells, and the harmful signals they generate, is one of the root causes of degenerative aging. There is a good amount of evidence for senescent cells to contribute to osteoporosis, of which the most compelling is that osteoporosis can be partially reversed in mice through targeted clearance of these unwanted cells. The study here is a different view into the link between cellular senescence and bone loss, with a focus on the autoimmune condition rheumatoid arthritis. While not an age-related disease, rheumatoid arthritis is associated with a greater risk of osteoporosis and greater number of senescent T cells. As such it is a useful point of comparison with normal aging.
Bone loss is one of the most common comorbidities of patients with rheumatoid arthritis (RA). Depending on the population studied, 10-56% of RA patients suffer from osteoporosis. In healthy individuals, bone homeostasis is maintained by a balance between bone formation and bone resorption. A link between inflammation and bone loss has been suggested for decades, and it was supported by in vitro observations and animal models showing enhanced bone resorption under the influence of pro-inflammatory cytokines. T-cells are one of the most important promoters of osteoclastogenesis, and the first evidence for the capacity of T-cells to cause bone loss was provided in 1999 by illustrating that T-cell-produced RANKL triggered osteoclastogenesis directly in a mouse model of arthritis. More recently, another study showed that T-cell-deficient mice were resistant to bone loss.
Premature immunosenescence including the accumulation of senescent CD4+ T-cells seems to be a hallmark feature of RA. Senescent T-cells are characterized by the loss of CD28, eroded telomeres, the lower content of T-cell receptor excision circles, the expression of pro-inflammatory molecules, and the gain of effector functions. Notably, senescent CD28- T-cell prevalence correlated with disease severity in RA. The role of immunosenescence in the context of osteoporosis, however, is elusive so far. The aim of this study was to investigate whether senescent CD4+28- T-cells are associated with early bone loss in RA patients.
We show that patients with systemic bone loss have a higher prevalence of circulating senescent CD4+CD28- T-cells than individuals with normal bone mineral density (BMD). RANKL is expressed at higher levels on senescent CD4+ T-cells compared to that on CD28+ T-cells, and its production can be stimulated with IL-15, a key cytokine in the pathogenesis of RA. Senescent CD4+ T-cells induce osteoclastogenesis more efficiently than CD28+ T-cells. Several studies demonstrated that T-cells are involved in the bone-remodeling system and that RANKL-expressing T-cells promote local and systemic osteoporosis. Besides, it has been demonstrated that senescent CD4+ T-cells were increased in patients with severe disease manifestations, and at the same time, these patients were at an increased risk of osteoporosis. These findings support our conclusion that senescent CD4+CD28- T-cells play an important role in the promotion of osteoporosis in RA as well as in non-RA individuals. Interestingly, we observed similar frequencies of CD4+CD28- T-cells in our RA and non-RA cohorts.