Inhibition of antigen presentation and T cell costimulation blocks PTH-induced bone loss

• Authors: Brahmchetna Bedi, Emory University; Jau-Yi Li, Emory University; Hesham Tawfeek, Emory University; M Neale Weitzmann, Emory University; Roberto Pacifici, Emory University
• Journal Title: Annals of the New York Academy of Sciences
• Volume: Volume 1192
• Publisher: New York Academy of Sciences | 2010-03, Pages 215-221
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/j.1749-6632.2009.05216.x
• Subjects: Health Sciences, Immunology; Health Sciences, Medicine and Surgery
• Keywords: parathyroid hormone; bone loss; T cell; lymphocyte; bone resorption

Abstract

T cells are required for continuous PTH (cPTH) treatment to induce bone loss as they sensitize SCs to PTH through CD40 Ligand (CD40L), a surface molecule of activated T cells. Since CD40L expression is a feature of activated T cells, we investigated whether antigen (Ag) mediated T cell activation is required for PTH to exert its catabolic activity. We report that inhibition of Ag presentation through silencing of either class I or class II MHC-T cell receptor (TCR) interaction prevents the cortical bone loss induced by in vivo cPTH treatment. We also show that the bone loss and the stimulation of bone resorption induced by cPTH treatment are prevented by CTLA4-Ig, an inhibitor of T cell costimulation approved for the treatment of Rheumatoid Arthritis. Since inhibition of antigen driven T cell activation by blockade of either TCR signaling or T cell costimulation is sufficient to silence the catabolic activity of cPTH, antigen presenting cells and T lymphocyte interactions therefore play a critical role in the mechanism of action of PTH.