CTLA-4Ig-Induced T Cell Anergy Promotes Wnt-10b Production and Bone Formation in a Mouse Model

Autor: Majd Zayzafoon, Susanne Roser-Page, M. Neale Weitzmann, Tatyana Vikulina
Rok vydání: 2014
Předmět:
Zdroj: Arthritis & Rheumatology. 66:990-999
ISSN: 2326-5191
DOI: 10.1002/art.38319
Popis: RA is a chronic inflammatory autoimmune disease that leads to bone loss around inflamed joints, as well as a generalized systemic osteoporosis (1–3). Lymphocytes play central roles not only in the initiation and progression of the inflammatory state, but also in the bone loss associated with RA (4–8). Lymphocytes drive bone turnover as a consequence of the immuno-skeletal interface, an enigmatic centralization of immune and skeletal functions around common cell types and cytokine effectors (9). Immune cells including T-cells, B-cells, and antigen presenting cells (APC) are implicated in the regulation of basal (10) and/or pathological bone turnover (11). Activated lymphocytes induce bone resorption by secreting Receptor activator of NF-κB ligand (RANKL), the key osteoclastogenic cytokine, and inflammatory factors including TNFα, a key driver of inflammatory cascades in RA. In addition, activated T cells produce Secreted osteoclastogenic factor of activated T-cells (SOFAT), a RANKL-independent osteoclastogenic cytokine, that may contribute to bone loss in RA (12, 13) and in periodontal infection (14). In contrast, under physiological conditions lymphocytes are protective of the skeleton, as both human (15) and rodent B-cells (9, 10) secrete the RANKL decoy receptor Osteoprotegerin (OPG). Because T-cell costimulatory interactions amplify B-cell OPG production (10, 15) disruptions to adaptive immune function can lead to RANKL/OPG imbalances permissive for osteoclastogenesis. Indeed, alterations to the immuno-skeletal interface causing a B-cell inversion in OPG and RANKL production may account, in part, for bone loss characteristic of HIV-infection (9, 16, 17). T-cells express several unique receptors/ligands necessary for immune regulation including the CD28 receptor, that binds to CD80/CD86 ligands expressed by APCs and mediates signals necessary for T-cell activation following binding of the T-cell receptor (TCR) to antigen bearing MHC complexes. Failure to activate CD28, or inhibition of CD28 signaling by CTLA4, a physiological modulator homologous to CD28 that competes for its ligands, leads to abortive T-cell activation and/or terminates immune responses resulting in T-cell anergy or deletion (18, 19). CTLA4-Ig (Abatacept), an anti-inflammatory pharmaceutical comprising the binding domain of human CTLA4 fused to human IgG1, is approved for treatment of refractory RA in adults (20) and for juvenile idiopathic arthritis in children (21). Our group has reported that CTLA4-Ig mitigates ovariectomy-induced bone loss by reducing T-cell activation and expression of TNFα by disrupting communication between T-cells and dendritic cells (22). Similarly, CTLA4-Ig ameliorates bone loss in mice treated with continuous infusion of PTH, a model of hyperparathyroidism (23). Furthermore, CTLA4-Ig is reported to directly suppress osteoclast differentiation in the absence of T-cells in vitro and to inhibit inflammatory bone erosion in vivo in an animal model of RA (24). Because CTLA4-Ig disrupts co-stimulatory interactions between B-cells and T-cells, it has the potential to not only lower immune activation responsible for driving inflammation, but also to disrupt basal bone turnover by disturbing the immuno-skeletal interface and B-cell OPG production. This effect has the potential to offset the gains in bone mass associated with reduced inflammation. In this study we investigated the net effect of CTLA4-Ig on basal bone turnover and mass in mice by quantifying indices of bone structure and turnover. CTLA4-Ig led to significant bone accrual but surprisingly as a consequence of increased bone formation, as a likely consequence of T-cell expression of the bone anabolic ligand Wnt10b. Our data show for the first time that CTLA4-Ig leads to induction of bone formation and may have potential applications as a novel bone anabolic agent.
Databáze: OpenAIRE
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