Abstract
Activated lymphocytes promote inflammation and bone destruction in rheumatoid arthritis (RA), making T cells and B cells therapeutic targets. Indeed, pharmacological blockade of CD28 costimulation using CTLA-4Ig (abatacept), approved for amelioration of RA, renders T cells dormant (anergic). CTLA-4Ig also promotes bone accretion in healthy mice; surprisingly, however, this effect is driven exclusively through upregulation of bone formation, rather than anti-inflammatory effects on resorption. In the study presented here, we utilized T cell receptor β gene and Wnt-10b gene knockout mice to investigate the roles of T cells and Wnt-10b in CTLA-4Ig–induced bone anabolism. Ablation of either T cells or Wnt-10b not only abolished CTLA-4Ig–induced bone anabolism but also, paradoxically, suppressed bone formation leading to bone loss. Stalled bone formation was accompanied by bone marrow stromal cell expression of the Wnt pathway inhibitor sclerostin. Our data suggest that an immunoskeletal pivot may promote or suppress bone formation, depending on the net outcome of CTLA-4Ig action directed independently on T cells and osteoblast-linage cells that counter Wnt-10b–induced bone anabolism, by secretion of sclerostin. While CTLA-4Ig action is tipped in favor of bone formation under physiological conditions, pathological immunodeficiency may lead to suppressed bone formation and skeletal damage.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 21-33 |
| Number of pages | 13 |
| Journal | Annals of the New York Academy of Sciences |
| Volume | 1415 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2018 |
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). M.N.W. was also supported, in part, by NIAMS Grants (AR056090, AR059364, AR068157, and AR070091) and NIA Grant AG040013. G.R.B. was supported by BLRD Grant number I01BX002363. R.P. was supported in part, by NIH Grants (DK108842, AR054625, and RR028009). The contents of this manuscript do not represent the views of the Department of Veterans Affairs, the National Institutes of Health, or the United States Government. M.N.W. designed the studies, interpreted the data, and wrote the manuscript. S.R-P., T.V., D.W., M.M.H., and G.R.B. performed the research. R.P. and T.F.L. provided unique reagents necessary to undertake the studies. All authors read, provided intellectual input, and approved the final manuscript.
Keywords
- CTLA-4Ig
- T cells
- Wnt-10b
- abatacept
- osteoblasts
ASJC Scopus subject areas
- General Neuroscience
- General Biochemistry, Genetics and Molecular Biology
- History and Philosophy of Science