000199610 001__ 199610
000199610 005__ 20181203023518.0
000199610 0247_ $$2doi$$a10.1126/scitranslmed.3007764
000199610 022__ $$a1946-6234
000199610 02470 $$2ISI$$a000335516300002
000199610 037__ $$aARTICLE
000199610 245__ $$aT Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway
000199610 260__ $$bAmer Assoc Advancement Science$$c2014$$aWashington
000199610 269__ $$a2014
000199610 300__ $$a10
000199610 336__ $$aJournal Articles
000199610 520__ $$aBone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany$$aBozec, Aline
000199610 700__ $$0244163$$g202817$$uUniv Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany$$aZaiss, Mario M.
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany$$aKagwiria, Rosebeth
000199610 700__ $$uUniv Freiburg, Dept Rheumatol & Clin Immunol, D-79085 Freiburg, Germany$$aVoll, Reinhard
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Paediat, D-91054 Erlangen, Germany$$aRauh, Manfred
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany$$aChen, Zhu
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany$$aMueller-Schmucker, Sandra
000199610 700__ $$uRobert Koch Inst, D-13353 Berlin, Germany$$aKroczek, Richard A.
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Dermatol, D-91054 Erlangen, Germany$$aHeinzerling, Lucie
000199610 700__ $$uUniv Libre Brussels, Dept Mol Biol, B-6041 Gosselies, Belgium$$aMoser, Muriel
000199610 700__ $$uGeorgia Regents Univ, Augusta, GA 30912 USA$$aMellor, Andrew L.
000199610 700__ $$aDavid, Jean-Pierre
000199610 700__ $$uUniv Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany$$aSchett, Georg
000199610 773__ $$j6$$tScience Translational Medicine$$k235
000199610 909C0 $$xU11270$$0252451$$pGHI
000199610 909CO $$pSV$$particle$$ooai:infoscience.tind.io:199610
000199610 937__ $$aEPFL-ARTICLE-199610
000199610 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000199610 980__ $$aARTICLE