==== Front Cell Death Dis Cell Death Dis Cell Death & Disease 2041-4889 Nature Publishing Group UK London 3250 10.1038/s41419-020-03250-x Editorial Linking glucocorticoid-induced osteoporosis to osteoimmunology http://orcid.org/0000-0002-2753-8738von Gunten Stephan stephan.vongunten@pki.unibe.ch http://orcid.org/0000-0002-9404-7736Simon Hans-Uwe grid.5734.50000 0001 0726 5157Institute of Pharmacology, University of Bern, Bern, Switzerland 14 12 2020 14 12 2020 12 2020 11 12 10263 11 2020 5 11 2020 13 11 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Subject terms Cell biologyImmunologyissue-copyright-statement© The Author(s) 2020 ==== Body Over millions of years, the skeletal and the immune systems have coevolved in the development from bony fish to terrestrial animals to form a symbiotic and highly interactive relationship. It has been suggested that environmental pressures, such as higher levels of UV light and oxygen, or lower levels of calcium in the terrestrial environment, promoted the establishment of the protective endosteal niche for haematopoietic stem cells (HSCs) in the bone marrow1. Besides other aspects, the tight connection between the immune and the skeletal systems is reflected by the following facts: (1) origination of osteoclasts from hematopoietic progenitor cells, (2) colocalization of osteoblast and osteoclast progenitor cells with immune cell progenitor and memory cells in the bone marrow, (3) immunomodulatory effects of the major pro-osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) and its expression by both osteoblast lineage cells and lymphocytes, (4) reciprocal effects of immune and bone remodelling cells in cell differentiation and bone remodelling, and (5) reduction of bone mass in inflammatory disorders, eventually as a consequence of excessive bone resorption2. In the last two decades, significant new insights into the complex interaction between the immune and skeletal systems brought light to the research field, which was referred to as ‘osteoimmunology’ by Arron and Choi in 20003. Glucocorticoids (GCs) exhibit a plethora of genomic and non-genomic effects in different tissues4, and significantly influence both bone remodelling and immune cells. High GC exposure, as it occurs in steroid therapy, has catabolic effects on bones and can result in osteoporosis. In fact, GC-induced osteoporosis (GIOP) is the most frequent cause of secondary osteoporosis5. The pharmacological effects of exogenous GCs in osteoporosis induction remain only partly understood, yet may include negative effects on differentiation, proliferation, survival, and function of osteoblasts and osteocytes, eventually involving Wnt signalling pathways, the transcription factors AP-1 and Notch, as well as specific miRNAs5. Besides direct effects on osteoclasts and their precursors, GCs may stimulate osteoclastogenesis by induction of RANKL and reduce expression of osteoprotegerin (OPG), a decoy receptor of RANKL, in osteoblastic cells and osteocytes6–8. In this issue of Cell Death and Disease, Song et al.9 report a central role of T cells for GIOP (Fig. 1). Using models with T-cell-deficient SCID or nude mice, they demonstrated that T cells are indispensable for the establishment of GIOP. SCID mice develop osteoporosis upon adoptive transfer of T cells, which was paralleled by an increase of RANKL in serum. T cells homing in the bone marrow were found to express RANKL and were able to stimulate ex vivo the differentiation of osteoclasts in co-culture experiments with myeloid RAW264.7 cells. Given that in other types of osteoporosis T-cell-derived cytokines have been shown to enhance RANKL expression in osteoblasts and other cells10,11, it is possible that such indirect effects also contribute mechanistically to the development of GIOP.Fig. 1 Proposed involvement of T cells in glucocorticoid-induced osteoporosis. While peripheral T cells may undergo apoptosis upon exposure to dexamethasone, some T cells accumulate in the bone marrow in a CXCL10-CXCR3 axis-dependent manner. Latter T cells are protected from cell death and promote RANKL-induced osteoclastogenesis. Illustration by Aldona von Gunten. GIOP glucocorticoid-induced osteoporosis, RANK receptor activator of NF-κB, RANKL RANK ligand. Peripheral lymphopenia can result from impaired lymphopoiesis in the endosteal niche due to diminished IL-7 production by osteoblasts, as observed under septic conditions12. In contrast, while dexamethasone treatment resulted in the reduction of circulating T-cell numbers and an increase of apoptotic T cells in the spleen, Song et al.9 observed an accumulation of viable T cells in the bone marrow, suggesting a protective influence of the endosteal niche. The increased T-cell homing to the bone marrow was found to be dependent on chemokine ligand receptor interactions with significant involvement of the CXCL10-CXCR3 axis. CXCL10 and CXCR3 receptor signalling have previously been linked to bone loss related to increased osteoclast differentiation and activity in various models of disease2, including conditions with an established pathogenic role of T cells. The study by Song et al. highlights the importance of T cells in the pathogenesis of GIOP and may support the consideration of osteoimmunological approaches in the prevention of GIOP. However, while the existing literature documents distinct contributions of T-cell subsets, cytokines, and chemokines in the development of osteoporosis1,10,11, their relevance to GIOP remain to be explored. Furthermore, it will be important to consider that significant differences in immune responses exist not only between species13,14, but also among human individuals15,16. Future pharmacotherapeutic strategies are expected to be inspired by a better understanding of molecular networks17, and the mutual interactions between the bone and immune systems in GIOP, eventually resulting in more personalized approaches to steroid therapy. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Conflict of interest The authors declare that they have no conflict of interest. ==== Refs References 1. Tsukasaki M Takayanagi H Osteoimmunology: evolving concepts in bone-immune interactions in health and disease Nat. Rev. Immunol. 2019 19 626 642 10.1038/s41577-019-0178-8 31186549 2. Brylka LJ Schinke T Chemokines in physiological and pathological bone remodeling Front. Immunol. 2019 10 2182 10.3389/fimmu.2019.02182 31572390 3. Arron JR Choi Y Bone versus immune system Nature 2000 408 535 536 10.1038/35046196 11117729 4. von Gunten S Mechanisms and potential therapeutic targets in allergic inflammation: recent insights Allergy 2013 68 1487 1498 10.1111/all.12312 24215555 5. Ahmad M A jack of all trades: impact of glucocorticoids on cellular cross-talk in osteoimmunology Front. Immunol. 2019 10 2460 10.3389/fimmu.2019.02460 31681333 6. Boutros C Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination Nat. Rev. Clin. Oncol. 2016 13 473 486 10.1038/nrclinonc.2016.58 27141885 7. Hofbauer LC Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL Arthritis Rheum. 2009 60 1427 1437 10.1002/art.24445 19404943 8. Piemontese M Xiong J Fujiwara Y Thostenson JD O’Brien CA Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice Am. J. Physiol. Endocrinol. Metab. 2016 311 E587 E593 10.1152/ajpendo.00219.2016 27460899 9. Song, L. et al. The critical role of T cells in glucocorticoid-induced osteoporosis. Cell Death Dis. 10. Walsh MC Takegahara N Kim H Choi Y Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity Nat. Rev. Rheumatol. 2018 14 146 156 10.1038/nrrheum.2017.213 29323344 11. Weitzmann MN Ofotokun I Physiological and pathophysiological bone turnover—role of the immune system Nat. Rev. Endocrinol. 2016 12 518 532 10.1038/nrendo.2016.91 27312863 12. Terashima A Sepsis-induced osteoblast ablation causes immunodeficiency Immunity 2016 44 1434 1443 10.1016/j.immuni.2016.05.012 27317262 13. D’Amelio P Sassi F Osteoimmunology: from mice to humans Bonekey Rep. 2016 5 802 10.1038/bonekey.2016.29 27195109 14. Schneider C IVIG regulates the survival of human but not mouse neutrophils Sci. Rep. 2017 7 1296 10.1038/s41598-017-01404-0 28465620 15. von Gunten S Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment Blood 2005 106 1423 1431 10.1182/blood-2004-10-4112 15827126 16. Luetscher RND Unique repertoire of anti-carbohydrate antibodies in individual human serum Sci. Rep. 2020 10 15436 10.1038/s41598-020-71967-y 32963315 17. von Gunten S The future of pharmacology: towards more personalized pharmacotherapy and reverse translational research Pharmacology 2020 105 1 2 10.1159/000505216 31822007