T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling.
Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here, we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells and induces these lymphocytes to activate canonical Wnt signaling in preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T-cell-produced Wnt10b. Therefore, T-cell-mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast crosstalk pathways may provide pharmacological targets for bone anabolism.
Terauchi
Masakazu
M
Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Li
Jau-Yi
JY
Bedi
Brahmchetna
B
Baek
Ki-Hyun
KH
Tawfeek
Hesham
H
Galley
Sarah
S
Gilbert
Linda
L
Nanes
Mark S
MS
Zayzafoon
Majd
M
Guldberg
Robert
R
Lamar
David L
DL
Singer
Meredith A
MA
Lane
Timothy F
TF
Kronenberg
Henry M
HM
Weitzmann
M Neale
MN
Pacifici
Roberto
R
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
D010281:Parathyroid Hormone; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse