Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice

Mingcan Yu; Patrizia D'Amelio; Abdul Malik Tyagi; Chiara Vaccaro; Jau-Yi Li; Emory Hsu; Ilaria Buondonno; Francesca Sassi; Jonathan Adams; M Neale Weitzmann; Richard DiPaolo; Roberto Pacifici

doi:10.15252/embr.201744421

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice

EMBO Rep. 2018 Jan;19(1):156-171. doi: 10.15252/embr.201744421. Epub 2017 Nov 20.

Authors

Affiliations

¹ Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA, USA.
² Gerontology Section, Department of Medical Sciences, University of Torino, Torino, Italy.
³ Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, USA.
⁴ Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁵ Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA, USA [email protected].
⁶ Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, GA, USA.

Abstract

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine.

Keywords: bone; bone formation; parathyroid hormone; regulatory T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Animals
Biomarkers / metabolism
Bone Density Conservation Agents / therapeutic use*
Calcium / therapeutic use
Calcium-Regulating Hormones and Agents / therapeutic use*
Collagen Type I / genetics
Collagen Type I / metabolism
Core Binding Factor Alpha 1 Subunit / genetics
Core Binding Factor Alpha 1 Subunit / metabolism
Disease Models, Animal
Female
Gene Expression
Humans
Integrin-Binding Sialoprotein / genetics
Integrin-Binding Sialoprotein / metabolism
Lymphocyte Count
Mice
Osteocalcin / genetics
Osteocalcin / metabolism
Osteoporosis, Postmenopausal / drug therapy*
Osteoporosis, Postmenopausal / genetics
Osteoporosis, Postmenopausal / metabolism
Osteoporosis, Postmenopausal / pathology
Ovariectomy
Sp7 Transcription Factor / genetics
Sp7 Transcription Factor / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / metabolism
Teriparatide / therapeutic use*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism
Treatment Outcome
Vitamin D / analogs & derivatives
Vitamin D / therapeutic use

Substances

Biomarkers
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents
Collagen Type I
Core Binding Factor Alpha 1 Subunit
Integrin-Binding Sialoprotein
Runx2 protein, mouse
Sp7 Transcription Factor
Sp7 protein, mouse
Transforming Growth Factor beta
Osteocalcin
Teriparatide
Vitamin D
25-hydroxyvitamin D
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding