T Cell-expressed CD40L Potentiates the Bone Anabolic Activity of Intermittent PTH Treatment

Overview

Journal J Bone Miner Res

Publisher Oxford University Press

Date 2014 Nov 1

PMID 25359628

Citations 22

Authors

Jerid W Robinson

Jau-Yi Li

Lindsey D Walker

Abdul Malik Tyagi

Michael A Reott

Mingcan Yu

Jonathan Adams

M Neale Weitzmann

Roberto Pacifici

Affiliations

Soon will be listed here.

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.

Citing Articles

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche.

Liu H, Liu L, Rosen C Cells. 2024; 13(5.

PMID: 38474370 PMC: 10930661. DOI: 10.3390/cells13050406.

The role of WNT10B in physiology and disease: A 10-year update.

Perkins R, Singh R, Abell A, Krum S, Miranda-Carboni G Front Cell Dev Biol. 2023; 11:1120365.

PMID: 36814601 PMC: 9939717. DOI: 10.3389/fcell.2023.1120365.

The immune factors have complex causal regulation effects on bone mineral density.

Cao R, Yu X, Xiong M, Li X, Deng F, Lei S Front Immunol. 2022; 13:959417.

PMID: 36341399 PMC: 9630477. DOI: 10.3389/fimmu.2022.959417.

The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cell homing to bone.

Pal S, Perrien D, Yumoto T, Faccio R, Stoica A, Adams J J Clin Invest. 2022; 132(12).

PMID: 35503658 PMC: 9197523. DOI: 10.1172/JCI157340.

Anabolic actions of PTH in murine models: two decades of insights.

Zweifler L, Koh A, Daignault-Newton S, McCauley L J Bone Miner Res. 2021; 36(10):1979-1998.

PMID: 34101904 PMC: 8596798. DOI: 10.1002/jbmr.4389.

References

Zhu N, Ramirez L, Lee R, Magnuson N, Bishop G, Gold M . CD40 signaling in B cells regulates the expression of the Pim-1 kinase via the NF-kappa B pathway. J Immunol. 2002; 168(2):744-54. DOI: 10.4049/jimmunol.168.2.744. View

Prasad K, Andre P, He M, Bao M, Manganello J, Phillips D . Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci U S A. 2003; 100(21):12367-71. PMC: 218764. DOI: 10.1073/pnas.2032886100. View

Quezada S, Jarvinen L, Lind E, Noelle R . CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol. 2004; 22:307-28. DOI: 10.1146/annurev.immunol.22.012703.104533. View

Drake M, Srinivasan B, Modder U, Ng A, Undale A, Roforth M . Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women. Bone. 2011; 49(3):349-55. PMC: 3143310. DOI: 10.1016/j.bone.2011.05.003. View

Grewal I, Flavell R . CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998; 16:111-35. DOI: 10.1146/annurev.immunol.16.1.111. View

Di Rosa F, Pabst R . The bone marrow: a nest for migratory memory T cells. Trends Immunol. 2005; 26(7):360-6. DOI: 10.1016/j.it.2005.04.011. View

Tobimatsu T, Kaji H, Sowa H, Naito J, Canaff L, Hendy G . Parathyroid hormone increases beta-catenin levels through Smad3 in mouse osteoblastic cells. Endocrinology. 2006; 147(5):2583-90. DOI: 10.1210/en.2005-1627. View

Guo J, Liu M, Yang D, Bouxsein M, Saito H, Galvin R . Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab. 2010; 11(2):161-71. PMC: 2819982. DOI: 10.1016/j.cmet.2009.12.007. View

Lopez-Granados E, Temmerman S, Wu L, Reynolds J, Follmann D, Liu S . Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A. 2007; 104(12):5056-61. PMC: 1817828. DOI: 10.1073/pnas.0605715104. View

10.

Schirrmacher V, Feuerer M, Fournier P, Ahlert T, Umansky V, Beckhove P . T-cell priming in bone marrow: the potential for long-lasting protective anti-tumor immunity. Trends Mol Med. 2003; 9(12):526-34. DOI: 10.1016/j.molmed.2003.10.001. View

11.

Andre P, Prasad K, Denis C, He M, Papalia J, Hynes R . CD40L stabilizes arterial thrombi by a beta3 integrin--dependent mechanism. Nat Med. 2002; 8(3):247-52. DOI: 10.1038/nm0302-247. View

12.

Ma Y, Zeng Q, Donley D, Ste-Marie L, Gallagher J, Dalsky G . Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis. J Bone Miner Res. 2006; 21(6):855-64. DOI: 10.1359/jbmr.060314. View

13.

Pettway G, Meganck J, Koh A, Keller E, Goldstein S, McCauley L . Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation. Bone. 2008; 42(4):806-18. PMC: 2677418. DOI: 10.1016/j.bone.2007.11.017. View

14.

Li J, Walker L, Tyagi A, Adams J, Weitzmann M, Pacifici R . The sclerostin-independent bone anabolic activity of intermittent PTH treatment is mediated by T-cell-produced Wnt10b. J Bone Miner Res. 2013; 29(1):43-54. PMC: 4326235. DOI: 10.1002/jbmr.2044. View

15.

Ahuja S, Zhao S, Bellido T, Plotkin L, Jimenez F, Bonewald L . CD40 ligand blocks apoptosis induced by tumor necrosis factor alpha, glucocorticoids, and etoposide in osteoblasts and the osteocyte-like cell line murine long bone osteocyte-Y4. Endocrinology. 2003; 144(5):1761-9. DOI: 10.1210/en.2002-221136. View

16.

Gao Y, Wu X, Terauchi M, Li J, Grassi F, Galley S . T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab. 2008; 8(2):132-45. PMC: 2569843. DOI: 10.1016/j.cmet.2008.07.001. View

17.

Terauchi M, Li J, Bedi B, Baek K, Tawfeek H, Galley S . T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 2009; 10(3):229-40. PMC: 2751855. DOI: 10.1016/j.cmet.2009.07.010. View

18.

Yamaguchi M, Ogata N, Shinoda Y, Akune T, Kamekura S, Terauchi Y . Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice. Endocrinology. 2005; 146(6):2620-8. DOI: 10.1210/en.2004-1511. View

19.

Grammer A, Lipsky P . CD40-mediated regulation of immune responses by TRAF-dependent and TRAF-independent signaling mechanisms. Adv Immunol. 2000; 76:61-178. DOI: 10.1016/s0065-2776(01)76019-1. View

20.

Leveille C, Bouillon M, Guo W, Bolduc J, Sharif-Askari E, El-Fakhry Y . CD40 ligand binds to alpha5beta1 integrin and triggers cell signaling. J Biol Chem. 2006; 282(8):5143-51. DOI: 10.1074/jbc.M608342200. View