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  • Review Article
  • Published:

Physiological and pathophysiological bone turnover — role of the immune system

Nature Reviews Endocrinology volume 12, pages 518–532 (2016)Cite this article

Subjects

Key Points

  • Receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) are key downstream effectors of bone resorption; tumour necrosis factor (TNF) might synergize with RANKL to superinduce osteoclastic bone resorption

  • B cells, regulated by T cells, are a key source of basal OPG whereas activated T cells and B cells are key sources of TNF and RANKL in inflammatory conditions

  • Short-term antiresorptive therapies might safely prevent bone loss associated with combination antiretroviral therapy

  • Anergic and parathyroid-hormone-treated T cells secrete the protein Wnt-10b, which promotes bone formation

  • Novel therapeutic strategies targeting the immune system might promote bone formation and decrease bone resorption to manage osteoporotic bone loss and prevent fracture

Abstract

Osteoporosis develops when the rate of osteoclastic bone breakdown (resorption) exceeds that of osteoblastic bone formation, which leads to loss of BMD and deterioration of bone structure and strength. Osteoporosis increases the risk of fragility fractures, a cause of substantial morbidity and mortality, especially in elderly patients. This imbalance between bone formation and bone resorption is brought about by natural ageing processes, but is frequently exacerbated by a number of pathological conditions. Of importance to the aetiology of osteoporosis are findings over the past two decades attesting to a deep integration of the skeletal system with the immune system (the immuno–skeletal interface (ISI)). Although protective of the skeleton under physiological conditions, the ISI might contribute to bone destruction in a growing number of pathophysiological states. Although numerous research groups have investigated how the immune system affects basal and pathological osteoclastic bone resorption, recent findings suggest that the reach of the adaptive immune response extends to the regulation of osteoblastic bone formation. This Review examines the evolution of the field of osteoimmunology and how advances in our understanding of the ISI might lead to novel approaches to prevent and treat bone loss, and avert fractures.

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Figure 1: Role of the RANK–RANKL–OPG system in physiological osteoclast formation.
Figure 2: Role of the immuno–skeletal interface in physiological osteoclast formation.
Figure 3: Bone loss associated with HIV infection and initiated by cART.
Figure 4: Augmentation of oestrogen deficiency bone loss by changes in the immuno–skeletal interface.
Figure 5: T-cell anergy promotes Wnt-10b secretion and bone anabolism.

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Acknowledgements

The authors gratefully acknowledge research support from the Biomedical Laboratory Research and Development Service of the Veteran's Affairs Office of Research and Development (Grant BX000105 to M.N.W.) and National Institutes of Health grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059364, AR056090 and AR053607) and the National Institute on Aging (AG040013) to M.N.W. and I.O.

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Authors and Affiliations

  1. The Atlanta Department of Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, 30033, Georgia, USA

    M. Neale Weitzmann

  2. Department of Medicine, Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, 101 Woodruff Circle, 1305 WMB, Atlanta, 30322, Georgia, USA

    M. Neale Weitzmann

  3. Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, 30303, Georgia, USA

    Ighovwerha Ofotokun

  4. Grady Healthcare System, 80 Jesse Hill Jr Drive SE, Atlanta, 30303, Georgia, USA

    Ighovwerha Ofotokun

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Both authors researched data for the article, made substantial contributions to discussions of the content, and edited and/or reviewed the manuscript before submission. M.N.W. wrote the manuscript.

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Correspondence to M. Neale Weitzmann.

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M.N.W. has filed a patent on the use of abatacept for stimulating bone anabolism. I.O. declares no competing interests.

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Weitzmann, M., Ofotokun, I. Physiological and pathophysiological bone turnover — role of the immune system. Nat Rev Endocrinol 12, 518–532 (2016). https://doi.org/10.1038/nrendo.2016.91

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