T Cells Set Bone Response

Abstract

Continuous exposure to parathyroid hormone (PTH), such as occurs in hyperparathyroidism, causes bone loss, whereas intermittent exposure to PTH, which is a treatment for osteoporosis, increases bone volume. Gao et al . sought to understand the role of T cells in the bone response to PTH. T cells provide survival cues to bone-building osteoblasts, as well as to bone marrow stromal cells, which are the precursors of the osteoblasts. T cells also stimulate stromal cells and osteoblasts to produce cytokines that trigger differentiation of osteoclasts, the bone-resorbing cells. Thus, T cells and bone cells have a complex relationship. Gao et al . found that continuous PTH infusion into mice lacking T cells resulted in less bone loss and less bone resorption. Bone marrow cells cultured from T cell-deficient mice had fewer stromal cells than those from wild-type mice and failed to produce osteoclasts in response to PTH. However, osteoclastogenesis was dose-dependently restored by the addition of T cells, but only if the T cells were added at the time of plating. Stromal cells isolated from wild-type mice that had been exposed to PTH exhibited increased mRNA for RANKL, a cytokine that stimulates osteoclastogenesis, and decreased the mRNA for osteoprotegern (OPG), a decoy ligand of the RANKL receptor. This PTH-stimulated change in cytokine production was absent in cells from the T cell-deficient mice. CD40 is a receptor, which is present on the stromal cells, and responds to CD40L, which is present on the T cells. If the T cells lacked CD40L or the stromal cells lacked CD40, then PTH failed to stimulate osteoclastogenesis of cultured bone marrow cells. Furthermore, continuous PTH exposure in CD40L-deficient mice failed to cause bone loss. Thus, T cells appear to provide signals through CD40L to bone precursors that allow them to survive, alter their cytokine production profile, and increase their responsiveness to the osteoclastogenic activity of PTH. Y. Gao, X. Wu, M. Terauchi, J.-Y. Li, F. Grassi, S. Galley, X. Yang, M. N. Weitzmann, R. Pacifici, T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab. 8 , 132-145 (2008). [PubMed]