EP259 - ECE_2188 - CD4+ T cells senescence decreases bone density by changes in genes related to calcium and phosphorus homeostasis

Abstract

Bone serves as the primary reservoir of calcium and phosphorus in the body and undergoes continuous remodeling. During aging or in conditions of calcium and phosphorus imbalance caused by physiological or pathological processes, bone resorption may increase, negatively impacting bone density. Calcium and bone homeostasis are regulated by several hormones, including PTH, calcitonin, calcitriol, and FGF23, produced in different organs. Inflammaging, a state of low-grade chronic inflammation associated with aging, is considered a risk factor for age-related diseases such as osteoporosis. Accumulation of senescent cells during aging can impair tissue function through the development of a Senescence-Associated Secretory Phenotype (SASP). Mice lacking expression of the mitochondrial gene Tfam specifically in CD4+ T cells exhibit T cell senescence and a premature aging phenotype. In this study, we investigated how senescent CD4+ T cells influence bone remodeling. Gene expression was analyzed by real-time PCR in tibiae from CD4-TFAM mice (Tfamfl/fl Cd4Cre/Cre) and control littermates, kindly provided by Dr. Mittelbrunn's research group (Centro de Biología Molecular Severo Ochoa, Madrid, Spain). Bone morphology was assessed using micro-computed tomography (micro-CT). Additionally, MLO-Y4 cells, an osteocyte model, were treated with 1% serum from CD4-TFAM or control mice, and gene expression was analyzed by real-time PCR. CD4-TFAM mice exhibited significantly lower bone mineral density and compromised bone structural integrity compared with controls. In bone tissue, the OPG/RANKL ratio and expression of osteocyte (osteocalcin) and osteoblast markers (alkaline phosphatase and Runx2) were reduced in CD4-TFAM mice. Expression of hormone receptors such as PTH1R and VDR was also significantly lower, whereas FGF23 expression was higher in CD4-TFAM mice. MLO-Y4 cells treated with serum from CD4-TFAM mice showed significantly increased RANKL expression, while VDR expression remained unchanged compared to cells treated with control serum. Mice with senescent CD4+ T cells displayed reduced bone mineral density and impaired structural integrity, likely due to enhanced osteoclastic activity at the expense of osteoblast function, combined with diminished responsiveness to hormonal regulation resulting from decreased receptor expression.