Bone and the Immune System

• Published in: Toxicologic pathology 2017-10, Vol.45 (7), p.911-924
• Main Author: Weitzmann, M. Neale
• Format: Article
• Language: English
• Subjects: Animals; Antiretroviral Therapy, Highly Active - adverse effects; Bone and Bones - drug effects; Bone and Bones - immunology; Bone and Bones - physiology; Bone Remodeling - drug effects; Bone Remodeling - immunology; Bone Resorption - drug therapy; Bone Resorption - immunology; Cytokines - metabolism; Estrogens - blood; Estrogens - deficiency; HIV Infections - complications; HIV Infections - drug therapy; Humans; Immune System; Lymphocytes - immunology; NF-kappa B - metabolism; Osteoclasts - metabolism; Osteoprotegerin - metabolism; Parathyroid Hormone - physiology; RANK Ligand - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623317735316

Osteoporosis increases fracture risk, a cause of crippling morbidity and mortality. The immunoskeletal interface (ISI) is a centralization of cell and cytokine effectors shared between skeletal and immune systems. Consequently, the immune system mediates powerful effects on bone turnover. Physiologically, B cells secrete osteoprotegerin (OPG), a potent anti-osteoclastogenic factor that preserves bone mass. However, activated T cells and B cells secrete pro-osteoclastogenic factors including receptor activator of Nuclear factor-kappaB (NF-kB) ligand (RANKL), Interleukin (IL)-17A, and tumor necrosis factor (TNF)-α promoting bone loss in inflammatory states such as rheumatoid arthritis. Recently, ISI disruption has been linked to osteoporosis in human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), where elevated B cell RANKL and diminished OPG drive bone resorption. HIV-antiretroviral therapy paradoxically intensifies bone loss during disease reversal, as immune reconstitution produces osteoclastogenic cytokines. Interestingly, in estrogen deficiency, activated T cells secrete RANKL, TNF, and IL-17A that amplify bone resorption and contribute to postmenopausal osteoporosis. T cell–produced TNF and IL-17A further contribute to bone loss in hyperparathyroidism, while T cell production of the anabolic Wingless integration site (Wnt) ligand, Wnt10b, promotes bone formation in response to anabolic parathyroid hormone and the immunomodulatory costimulation inhibitor cytotoxic T lymphocyte–associated protein-4-IgG (abatacept). These findings provide a window into the workings of the ISI and suggest novel targets for future therapeutic interventions to reduce fracture risk.