Role of T cells in the modulation of PTH action: physiological and clinical significance

Abstract

Osteoimmunology is new field of research dedicated to the study of the interactions between the immune system and bone. Among the cells of the immune system that regulate bone and hemopoietic cells are T lymphocytes. These cells secrete osteoclastogenic cytokines such as RANKL and TNF, as well as factors that stimulate bone formation and hemopoietic cells, one of which is Wnt10b. This article will review the evidence that T cells are implicated in the mechanism of action of parathyroid hormone (PTH) in bone and on the hemopoietic system.

Figure 1

Schematic representation of the role of T cells in the mechanism by which continuous PTH induces bone loss. PTH binding to PPR in T cells stimulates the production of TNF. This cytokine increases CD40 expression by SCs. Binding of CD40 by T cell expressed CD40L increases SC sensitivity to PTH resulting in enhanced SC production of RANKL and diminished secretion of OPG in response to PTH. T cell produced TNF further stimulates OC formation through its direct effects on maturing OC precursors. The red arrows represent the main modifications induced by activation of PPR signaling in T cells. Reproduced with permission from H. Tawfeek eat al PLoS One, 2010. 5: e12290

Figure 2

Schematic representation of the role of T cells in the mechanism by which intermittent PTH treatment stimulates bone formation. PTH stimulates T cells to secrete Wnt10b, a Wnt ligand required to activate Wnt signaling in SCs and OBs. In the presence of T cell produced Wnt10b, stimulation of osteoblastic cells by PTH result in the activation of the Wnt signaling pathway. This event leads to increased commitment of mesenchymal stem cells to the osteoblastic lineage, increased osteoblast proliferation and differentiation, and decreased osteoblast apoptosis. Reproduced with permission from B. Bedi et al Proc. Natl. Acad. Scie. 2012. 109:E725–733

Figure 3

Schematic representation of the role of T cells in the mechanism by which intermittent PTH treatment stimulates HSPCs expansion. Direct PPR signaling in T cells stimulates T cells to secrete Wnt10b, a Wnt ligand required to activate Wnt signaling. In the presence of T cell produced Wnt10b, PTH activates Wnt signaling in stromal cells and HSPCs. Wnt signaling activation also upregulates the expression of the Notch ligand Jagged 1 in SCs. These events result in HSPCs expansion. Reproduced with permission from J. Li et al, Blood. 2012120: 4352–4362.