T-Cell Mediated Inflammation in Postmenopausal Osteoporosis

Abstract

Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause - the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.

Keywords: T cell; chronic inflammation; estrogen loss; osteoimmunology; postmenopausal osteoporosis.

Figure 1

Balance between immunogenic and tolergenic states is linked with resorptive and osteogenic states of the bone. Chronic inflammation may be derived by increases in effector T-cells (T_EFF) and effector memory T-cells (T_EM). Bone is very sensitive to TNFα and IL-17A produced by T-cells. Estrogen (E₂) prevents the conversion of T_M to T_EM. Tolerogenic T-cells (i.e., T_REG and Tc_REG) promote bone formation through direct and indirect mechanisms. All Figures were created with (BioRender.com).

Figure 2

Estrogen (E₂) regulates bone marrow resident memory T-cells (T_BRM) homeostasis and E₂ loss promotes conversion of T_BRM to T_EM. T_M migrate to and take up long-term residence in the bone marrow. Left panel: Bone marrow resident dendritic cells (BMDC) secrete IL-7, IL-15 or both to promote survival of T_M. In E₂ replete females, BMDC have a short lifespan because E₂ induces FasL in the BMDC. In addition, IL-15 induces Fas in proliferating T_M in response to IL-7 and IL-15 thus maintain a homeostatic pool of T_BRM. Right: In absence of E₂, Fas ligand (FasL) is no longer induced leading to increased lifespans of BMDC and high concentrations of IL-7 and IL-15. In the presence of high IL-7 and IL-15 and absence of FasL, all T_M proliferate and a subset (~5 to 10%) produce TNFα and IL-17A, which then promotes bone resorption and also limits bone formation.

Figure 3

Osteoclasts induce tolerogenic Tc_REG. This figure summarizes how OC induce Tc_REG to promote restore homeostasis under inflammatory conditions. OC use three signals: antigen-loaded MHC I that ligates TCR on CD8 T-cells, CD200 (a costimulation molecule that activates NF-κB) and the Notch ligand DLL4 that engages Notch1 and Notch4 on the T-cells. TNFα and/or IL-17A downregulate DLL4 expression on OC. Treatment with pRANKL leads to increased expression DLL4. Tc_REG secrete IFN-γ that suppress osteoclastogenesis by degrading TRAF6 and also suppress resorption by mature OC. Tc_REG also secrete IL-10, which is required for the bone anabolic activity but not resolution of inflammation. IL-10 may also target Ocy to improve cortical bone mass. Resolution of inflammation appears to be mediated by CTLA4 expressed on Tc_REG.