title: Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss.
abstract: BACKGROUND
  Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs.
  
  
  RESULTS
  Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor alpha (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio.
  
  
  CONCLUSIONS
  These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism.
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Hesham
authors.initials: H
authors.lastname: Tawfeek
authors.forename: Brahmchetna
authors.initials: B
authors.lastname: Bedi
authors.forename: Jau-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adams
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacifici
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000096:biosynthesis; D010281:Parathyroid Hormone / Q000494:pharmacology*; D053245:RANK Ligand / Q000096:biosynthesis; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D053245:RANK Ligand; D044168:Receptor, Parathyroid Hormone, Type 1; D014409:Tumor Necrosis Factor-alpha
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