T Cells Potentiate PTH-Induced Cortical Bone Loss through CD40L Signaling

Abstract

PTH promotes bone catabolism by targeting bone marrow stromal cells (SCs) and their osteoblastic progeny. Here we show that a continuous infusion of PTH that mimics hyperparathyroidism fails to induce osteoclast formation, bone resorption and cortical bone loss in mice lacking T cells. T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 Ligand (CD40L), a surface molecule of activated T cells that induces CD40 signaling in SCs. As a result, deletion of T cells or T cell expressed CD40L blunts the bone catabolic activity of PTH by decreasing bone marrow SC number, RANKL/OPG production and osteoclastogenic activity. Therefore, T cells play an essential permissive role in hyperparathyroidism as they influence SC proliferation, lifespan and function through CD40L. T cell-SC cross-talk pathways may thus provide pharmacological targets for PTH induced bone disease.

Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand

“…In fact, the current and previous reports from our laboratory (36,38) have disclosed that CD40L −/− mice have a lower bone volume than WT controls, primarily because stimulation of CD40 signaling in B cells by T cell-expressed CD40L induces OPG production, thus reducing bone resorption (36). These findings are concordant with studies in humans demonstrating that osteopenia is a frequent clinical feature of subjects with X-linked hyper-IgM syndrome, an inherited disorder caused by mutations in the gene encoding CD40L (37).…”

“…The CD40L-mediated T-cell/SC cross-talk has been previously shown to play a critical role in the bone loss induced by continuous infusion of PTH, which is a model of primary hyperparathyroidism (38). Therefore, it will be important to determine if the conditioning effect of CD40L on SCs contributes to bone loss in other skeletal diseases.…”

“…T-cell immunodepletion was achieved by initiating anti-CD4/8 Ab treatment 2 wk before surgery. This design was required because the conditioning effect of T cells on SCs persists for ∼2 wk (38). Postsurgical follow-up was limited to 2 wk because partial T-cell recovery was observed in a preliminary study after longer CD4/8 Ab treatment.…”

“…All the animal procedures were approved by the Institutional Animal Care and Use Committee of Emory University. WT mice were depleted of T cells in vivo as previously described (38). Effective depletion was confirmed by flow cytometry (Fig.…”

“…Low bone density has also been found in children affected by X-linked hyper-IgM syndrome, a condition in which CD40L production is impaired because of a mutation of the CD40L gene (37). Mice lacking T cell-expressed CD40L are protected against parathyroid hormone (PTH)-induced bone loss (38), however, raising the possibility that CD40L may exert antiresorptive activities in unstimulated conditions, although promoting bone resorption under conditions of bone stress.…”