Premature senescence of t-cells favors bone loss during osteolytic diseases. a new concern in the osteoimmunology arena

Luis González-Osuna, Alfredo Sierra-Cristancho, Carolina Rojas, Emilio A. Cafferata, Samanta Melgar-Rodríguez, Angélica M. Cárdenas, Rolando Vernal

Research output: Contribution to journalReview articlepeer-review

3 Scopus citations

Abstract

Cellular senescence is a biological process triggered in response to time-accumulated DNA damage, which prioritizes cell survival over cell function. Particularly, senescent T lymphocytes can be generated prematurely during chronic inflammatory diseases regardless of chronological aging. These senescent T lymphocytes are characterized by the loss of CD28 expression, a co-stimulatory receptor that mediates antigen presentation and effective T-cell activation. An increased number of premature senescent CD4+CD28- T lymphocytes has been frequently observed in osteolytic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, osteopenia, osteoporosis, and osteomyelitis. Indeed, CD4+CD28- T lymphocytes produce higher levels of osteoclastogenic molecular mediators directly related to pathologic bone loss, such as tumor necrosis factor (TNF)-α, interleukin (IL)-17A, and receptor-activator of nuclear factor κB ligand (RANKL), as compared with regular CD4+CD28+ T lymphocytes. In addition, premature senescent CD8+CD28- T lymphocytes have been negatively associated with bone healing and regeneration by inhibiting osteoblast differentiation and mesenchymal stromal cell survival. Therefore, accumulated evidence supports the role of senescent T lymphocytes in osteoimmunology. Moreover, premature senescence of T-cells seems to be associated with the functional imbalance between the osteolytic T-helper type-17 (Th17) and bone protective T regulatory (Treg) lymphocytes, as well as the phenotypic instability of Treg lymphocytes responsible for its trans-differentiation into RANKL-producing exFoxp3Th17 cells, a key cellular phenomenon directly related to bone loss. Herein, we present a framework for the understanding of the pathogenic characteristics of T lymphocytes with a premature senescent phenotype; and particularly, we revise and discuss their role in the osteoimmunology of osteolytic diseases.

Original languageEnglish
Pages (from-to)1150-1161
Number of pages12
JournalAging and Disease
Volume12
Issue number5
DOIs
StatePublished - 1 Aug 2021

Keywords

  • Bone loss
  • CD28
  • Osteoimmunology
  • RANKL
  • Senescence
  • T-lymphocytes

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