title: T cell-expressed CD40L potentiates the bone anabolic activity of intermittent PTH treatment.
abstract: T cells are known to potentiate the bone anabolic activity of intermittent parathyroid hormone (iPTH) treatment. One of the involved mechanisms is increased T cell secretion of Wnt10b, a potent osteogenic Wnt ligand that activates Wnt signaling in stromal cells (SCs). However, additional mechanisms might play a role, including direct interactions between surface receptors expressed by T cells and SCs. Here we show that iPTH failed to promote SC proliferation and differentiation into osteoblasts (OBs) and activate Wnt signaling in SCs of mice with a global or T cell-specific deletion of the T cell costimulatory molecule CD40 ligand (CD40L). Attesting to the relevance of T cell-expressed CD40L, iPTH induced a blunted increase in bone formation and failed to increase trabecular bone volume in CD40L(-/-) mice and mice with a T cell-specific deletion of CD40L. CD40L null mice exhibited a blunted increase in T cell production of Wnt10b and abrogated CD40 signaling in SCs in response to iPTH treatment. Therefore, expression of the T cell surface receptor CD40L enables iPTH to exert its bone anabolic activity by activating CD40 signaling in SCs and maximally stimulating T cell production of Wnt10b.
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Jerid W
authors.initials: JW
authors.lastname: Robinson
authors.forename: Jau-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Walker
authors.forename: Abdul Malik
authors.initials: AM
authors.lastname: Tyagi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Reott
authors.forename: Mingcan
authors.initials: M
authors.lastname: Yu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adams
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacifici
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D045930:Anabolic Agents; D010281:Parathyroid Hormone; D023201:CD40 Ligand
keywords: BM; BONE MARROW; OB; OSTEOBLAST; PARATHYROID HORMONE; PPR; PTH; PTH/PTHRP RECEPTOR; SC; STROMAL CELL