Research ArticleBONE DISEASE

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway

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Science Translational Medicine  07 May 2014:
Vol. 6, Issue 235, pp. 235ra60
DOI: 10.1126/scitranslmed.3007764

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A Bone to Pick with the Immune System

School children are often taught that bones are static, providing support for the body. However, bone is actually a very dynamic tissue, constantly being built up and broken down. When this process is out of balance, for example, with excessive resorption, bone disease such as osteoporosis or fracture occurs. Now, Bozec et al. describe a process by which the immune system helps to control bone resorption.

The authors found that the immune costimulatory molecules CD80/86 negatively regulate generation of bone-resorbing osteoclasts. Mice deficient in these molecules were osteopenic because of increased osteoclast differentiation. Mechanistically, CD80/86 stimulation resulted in activation of an enzyme—indoleamine 2,3-dioxygenase (IDO)—in osteoclast precursors, which degraded tryptophan and promoted osteoclast apoptosis. The authors then looked in humans that had been treated with either ipilimumab (a blocking antibody to CTLA-4, which binds CD80/86) or abatacept (a CTLA-4–Ig fusion protein). Consistent with their mouse data, they found that ipilimumab increased whereas abatacept reduced the frequency of osteoclasts. These data suggest that immune costimulatory molecules can regulate bone resorption and highlight potential skeletal effects of immune costimulation–targeting therapies.

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