Abstract
T-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. This 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. Patients 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. Our 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.
Highlights
Bone loss is one of the most common comorbidities of patients with rheumatoid arthritis (RA)
We investigated whether senescent T-cells express receptor activator of nuclear factor kappa-B ligand (RANKL), which is a key mediator of bone loss [19]
We show that patients with systemic bone loss have a higher prevalence of circulating senescent CD4+CD28− T-cells than individuals with normal BMD
Summary
Bone loss is one of the most common comorbidities of patients with rheumatoid arthritis (RA). Senescent T-Cells Promote Bone Loss [4]. 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 by Kong et al in 1999 by illustrating that T-cell-produced receptor activator of nuclear factor kappa-B ligand (RANKL) triggered osteoclastogenesis directly in a mouse model of adjuvant-induced arthritis [5]. Another study showed that T-cell-deficient mice were resistant to bone loss using a mouse model of postmenopausal osteoporosis [6]. Numerous other studies have investigated the potential role of T-cells to interfere with bone homeostasis [7, 8]
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