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Author Notes:

Correspondence to: M. Neale Weitzmann, Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, 101 Woodruff Circle, 1305 WMB, GA 30322-0001, USA. E-mail: mweitzm@emory.edu

Authors’ contributions: M.N.W. conceived the study, performed data analysis and drafted the manuscript.

S.R.-P., T.V., M.E.M.-L. and K.Y. performed data acquisition, data analysis and revised and finalized the manuscript.

All authors read and approved the final manuscript and gave consent for publication in the journal Rheumatology.

Acknowledgments: The authors thank Dr Daiana Weiss (Emory University) for critical reading of the manuscript and Ms Penny Roon and the Augusta University Electron Microscopy and Histology Core Laboratory for preparation of histological sections for histomorphometry.

Disclosure statement: The authors have declared no conflicts of interest.

The contents of this manuscript do not represent the views of the Department of Veterans Affairs.

Subjects:

Research Funding:

This work was supported by a grant from the Biomedical Laboratory Research & Development (BLRD) Service of the VA Office of Research and Development (5I01BX000105) to M.N.W.

M.N.W. was also supported, in part, by grants from the National Institutes of Health including the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers AR056090, AR059364, AR068157 and AR070091) and the National Institute on Aging (grant number AG040013).

M.E.M.-L. was supported by the National Institute on Aging (AG036675).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Rheumatology
  • osteoblast
  • T cell
  • Wnt-10b
  • CD40 ligand
  • MR1
  • bone formation
  • rheumatoid arthritis
  • CD8 T-CELLS
  • ANABOLIC ACTIVITY
  • B-CELLS
  • MECHANISMS
  • BLOCKADE
  • MODEL

Neutralization of CD40 ligand costimulation promotes bone formation and accretion of vertebral bone mass in mice

Journal Title:

Rheumatology

Volume:

Volume 57, Number 6

Publisher:

, Pages 1105-1114

Type of Work:

Article | Final Publisher PDF

Abstract:

Objective. Immunosuppressive biologics are used in the management of RA and additional immunomodulators are under investigation including modulators of the CD40/CD40 ligand (CD40L) costimulation pathway. Tampering with immune function can have unanticipated skeletal consequences due to disruption of the immuno-skeletal interface, a nexus of shared cells and cytokine effectors serving discrete functions in both immune and skeletal systems. In this study, we examined the effect of MR1, a CD40L neutralizing antibody, on physiological bone remodelling in healthy mice. Methods. Female C57BL6 mice were treated with MR1 and BMD was quantified by dual energy X-ray absorptiometry and indices of trabecular bone structure were quantified by micro-CT. Serum biochemical markers were used to evaluate bone turnover and formation indices by histomorphometry. Results. Unexpectedly, MR1 stimulated significant accretion of BMD and trabecular bone mass in the spine, but not in long bones. Surprisingly, bone accretion was accompanied by a significant increase in bone formation, rather than suppression of bone resorption. Mechanistically, MR1-induced bone accrual was associated with increased Treg development and elevated production of cytotoxic T lymphocyte antigen 4, a costimulation inhibitor that promotes T cell anergy and CD8+T cell expression of the bone anabolic ligand Wnt-10b. Conclusion. Our studies reveal an unexpected bone anabolic activity of pharmacological CD40L suppression. Therapeutic targeting of the CD40L pathway may indeed have unforeseen consequences for the skeleton, but may also constitute a novel strategy to promote bone formation to ameliorate osteoporotic bone loss and reduce fracture risk in the axial skeleton.

Copyright information:

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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