Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis

Abstract

ObjectiveT-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far.MethodsThis includes a prospective study of consecutive patients with RA (n = 107), patients with primary osteopenia/-porosis (n = 75), and healthy individuals (n = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4+CD28− T-cells.ResultsPatients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28− T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4+CD28− T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28− T-cells. CD4+CD28− T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells.ConclusionOur data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28+ T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.

Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression

“…RANKL, in combination with TNF-α, IL-6 and IL-1β, acts on the differentiation of osteoclasts and degrades mineralized bone matrix through protease synthesis [56]. Therefore, the expansion of peripheral senescent CD4+ T cells may impact bone mineral density and are negatively related to osteoporosis [55]. As previously discussed, CMV infection may worsen the clinical course and facilitate the development of extra-articular manifestations via the expansion of CD4 + CD28-T cells [39].…”

“…The expansion of the senescent CD4+ T cell population has been associated with increased bone loss and support of the early development of osteoporosis in RA. Indeed, CD4 + CD28-T lymphocytes from RA patients exhibit higher concentrations of the receptor activator of nuclear factor kappa-Β ligand (RANKL) than CD28+ cells [55]. RANKL, in combination with TNF-α, IL-6 and IL-1β, acts on the differentiation of osteoclasts and degrades mineralized bone matrix through protease synthesis [56].…”

Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines

“…A novel T-cell subset CD28 − Treg-like cell has been described that produce pro-inflammatory cytokines, mirroring the SASP associated with senescent cells ( 316 ). RA patients who show CD28 − senescent Treg-like cells in blood seem to demonstrate earlier and more severe osteoporosis ( 317 ).…”

C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation

“…It has been proposed to be involved in the clearance of pathogens or apoptotic cells ( 14 , 15 ), to induce pro-inflammatory cytokines ( 19 , 20 ), and to play a pathogenic role in cardiovascular diseases ( 21 ). At least some of the pro-inflammatory effects are mediated by activated CRP that exposes binding sites for complement and immunoglobulins and is mainly found within inflamed tissues ( 22 , 23 ). In contrast to the more pro-inflammatory functions, CRP induces high levels of the anti-inflammatory IL-1 receptor antagonist ( 24 ), and transgenic animals overexpressing human CRP are protected from inflammatory diseases including sepsis ( 25 ), alveolitis ( 26 ), arthritis ( 27 ), and atherosclerosis ( 28 ).…”