Background/Purpose:

To study the influence of senescent CD28^–T-cells on systemic osteoporosis in rheumatoid arthritis (RA) and patients with primary osteoporosis.

Methods:

Prospective, cross-sectional study on 104 patients with RA (mean age 62.2 [±SD 12.6], 76% female, SDAI 13.5 [±10.2]) and 111 non-RA controls (mean age 60.7 [±11.3], 84.7% female). Bone mineral density (BMD) was determined by DEXA. PBMCs were retrieved at the same day of BMD measurement and were stained with anti-RANKL, CD3, CD4, CD8, CD45RA, CD45RO and/or CD28 mAbs to measure surface and intracellular expression of RANKL on T-cells and to determine the prevalence of T-cell subsets by flow cytometry. The capacity of T-cell subsets to induce osteoclastogenesis was assessed via TRAP staining in the presence of monocytes and M-CSF (25ng/ml) in vitro.

Results:

A reduced BMD as determined by DEXA was found in 58.1% of RA patients (14% with osteoporosis, 44.1% with osteopenia) and 56.1% of non-RA controls (38.8% with osteoporosis, 17.3% with osteopenia). RA patients with reduced BMD had higher prevalences of circulating CD4⁺CD28^– (3.2% [0.1–41.2] vs. 0.7% [0.1–33.9], p=0.048). In non-RA controls we observed the same effect (3.5% [0.1–30.4] vs. 1.3% [0.1–34], p=0.032).

Surface RANKL expression was higher on CD4⁺CD28^– T-cells (3.1% [0-57.9]) compared to naïve CD4⁺CD28⁺CD45RA⁺ (1.5 [0-45.3], p<0.001) and memory CD4⁺CD28⁺CD45RO⁺ (1.9 [0-38], p=0.006) T-cells. Moreover, surface RANKL expression was higher in RA patients than non-RA controls in all T-cell subsets (all p<0.05). After stimulation with anti-CD3 antibody, RANKL production was higher in CD4⁺CD28^– T-cells (intracellular RANKL MFI: 870.2 [±205.9]) compared to naïve CD4⁺CD28⁺CD45RA⁺ (713 [±182.3], p=0.001) T-cells, whereas RANKL levels were similar in CD4⁺CD28^– T-cells and memory CD4⁺CD28⁺CD45RO⁺ (862.2 [±289.7], p=0.207) T-cells. Similar results were obtained after stimulation with PHA or ConA.

The in vitro ability of T-cell subsets to induce osteoclastogenesis was higher in senescent CD28^– T-cells compared to their CD28⁺ counterparts as indicated by TRAP-staining ((27.5 [±15.8] TRAP positive cells vs. 20.5 [±7.9], p=0.128).

Conclusion:

Senescent CD28^– T-cells are linked with the occurrence of systemic bone loss. Increased expression of RANKL on CD4⁺CD28^– T-cells compared to other T-cell subsets may result in higher direct stimulation of osteoclastogenesis by this subset.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/senescent-t-cells-expedite-rankl-dependent-bone-loss-in-rheumatoid-arthritis/