CTLA-4Ig (abatacept) balances bone anabolic effects of T cells and Wnt-10b with antianabolic effects of osteoblastic sclerostin

Autor:	Roberto Pacifici, Timothy F. Lane, Mark M. Habib, Susanne Roser-Page, Daiana Weiss, M. Neale Weitzmann, George R. Beck, Tatyana Vikulina
Rok vydání:	2018
Předmět:	030203 arthritis & rheumatology 0301 basic medicine Anabolism Chemistry General Neuroscience Abatacept Wnt signaling pathway CD28 Inflammation General Biochemistry Genetics and Molecular Biology Resorption 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine History and Philosophy of Science Downregulation and upregulation medicine Cancer research Sclerostin medicine.symptom medicine.drug
Zdroj:	Annals of the New York Academy of Sciences. 1415:21-33
ISSN:	0077-8923
DOI:	10.1111/nyas.13643
Popis:	Activated lymphocytes promote inflammation and bone destruction in rheumatoid arthritis (RA), making T cells and B cells therapeutic targets. Indeed, pharmacological blockade of CD28 costimulation using CTLA-4Ig (abatacept), approved for amelioration of RA, renders T cells dormant (anergic). CTLA-4Ig also promotes bone accretion in healthy mice; surprisingly, however, this effect is driven exclusively through upregulation of bone formation, rather than anti-inflammatory effects on resorption. In the study presented here, we utilized T cell receptor β gene and Wnt-10b gene knockout mice to investigate the roles of T cells and Wnt-10b in CTLA-4Ig-induced bone anabolism. Ablation of either T cells or Wnt-10b not only abolished CTLA-4Ig-induced bone anabolism but also, paradoxically, suppressed bone formation leading to bone loss. Stalled bone formation was accompanied by bone marrow stromal cell expression of the Wnt pathway inhibitor sclerostin. Our data suggest that an immunoskeletal pivot may promote or suppress bone formation, depending on the net outcome of CTLA-4Ig action directed independently on T cells and osteoblast-linage cells that counter Wnt-10b-induced bone anabolism, by secretion of sclerostin. While CTLA-4Ig action is tipped in favor of bone formation under physiological conditions, pathological immunodeficiency may lead to suppressed bone formation and skeletal damage.
Databáze:	OpenAIRE
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