CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse model.
OBJECTIVE
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by severe joint erosion and systemic osteoporosis. Chronic T cell activation is a hallmark of RA, and agents that target the CD28 receptor on T cells, which is required for T cell activation, are being increasingly used as therapies for RA and other inflammatory diseases. Lymphocytes play complex roles in the regulation of the skeleton, and although activated T cells and B cells secrete cytokines that promote skeletal decline, under physiologic conditions lymphocytes also have key protective roles in the stabilization of skeletal mass. Consequently, disruption of T cell costimulation may have unforeseen consequences for physiologic bone turnover. This study was undertaken to investigate the impact of pharmacologic CD28 T cell costimulation blockade on physiologic bone turnover and structure.


METHODS
C57BL6 mice were treated with CTLA-4Ig, a pharmacologic CD28 antagonist or with irrelevant control antibody (Ig), and serum biochemical markers of bone turnover were quantified by enzyme-linked immunosorbent assay. Bone mineral density and indices of bone structure were further measured by dual x-ray absorptiometry and micro-computed tomography, respectively, and static and dynamic indices of bone formation were quantified using bone histomorphometry.


RESULTS
Pharmacologic disruption of CD28 T cell costimulation in mice significantly increased bone mass and enhanced indices of bone structure, a consequence of enhanced bone formation, concurrent with enhanced secretion of the bone anabolic factor Wnt-10b by T cells.


CONCLUSIONS
Inhibition of CD28 costimulation by CTLA-4Ig promotes T cell Wnt-10b production and bone formation and may represent a novel anabolic strategy for increasing bone mass in osteoporotic conditions.
Atlanta VAMC, Decatur, Georgia.
Susanne
S
Roser-Page
Tatyana
T
Vikulina
Majd
M
Zayzafoon
M Neale
MN
Weitzmann
D000069594:Abatacept; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D018796:Immunoconjugates / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
D018796:Immunoconjugates; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D000069594:Abatacept