Increased RANKL expression in peripheral T cells is associated with decreased bone mineral density in patients with COPD

Receptor activator of nuclear factor-B ligand (RANKL)-expressing adaptive T cells contribute to bone damage in autoimmune arthritis, although their role in chronic obstructive pulmonary disease (COPD)-associated osteoporosis is unknown. In the present study, the functional expression of RANKL in CD4(+)/CD8(+) T cells and Th17 cells, and the potential role of these cells in COPD-associated bone loss was investigated. A total of 36 non-smokers, 38 smokers with normal lung function and 57 patients with COPD were enrolled. Femoral and vertebral bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry. RANKL expression in peripheral CD4(+) and CD8(+) T cells and Th17 cells was evaluated by flow cytometry. For in vitro experiments, CD4(+) and CD8(+) T cells from 17 non-smokers were evaluated for RANKL expression following dose-dependent culture with cigarette smoke extract (CSE) for 5 days. The frequencies of RANKL-positive CD4(+) and CD8(+) T cells were higher in the patients with COPD than in the non-smokers (P=0.001 and P=0.002, respectively). The proportion of CD4(+) T cells positive for both RANKL and interleukin-17 (IL-17) was higher in the patients with COPD than in the non-smokers (P=0.010). However, the frequency of RANKL-expressing Th17 cells was similar among all groups (P=0.508). The frequency of RANKL(+)CD4(+) T cells inversely correlated with BMD of the lumbar vertebrae (P=0.01, r=-0.229), and that of the femoral neck (P<0.001, r=-0.350). The results of our in vitro experiments revealed that CSE increased RANKL expression in CD4(+) T cells only. The percentages of RANKL-positive CD4(+) T cells and RANKL- and IL-17 double-positive CD4(+) T cells were increased in the peripheral blood of patients with COPD, and the former were associated with BMD. These observations suggest that RANKL(+)CD4(+) T cells may be mechanistically linked to diseases of the lung and bone in patients with COPD.