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FASEB J. 2013 Aug;27(8):2977-87. doi: 10.1096/fj.13-227264. Epub 2013 Apr 16.

Regulation and function of immunosuppressive molecule human leukocyte antigen G5 in human bone tissue.

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  • 1Stromalab Unité Mixte de Recherche (UMR) Université Paul Sabatier (UPS)/Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang (EFS)-Pyrénées-Méditerranée Toulouse, Toulouse, France.


Bone-marrow mesenchymal stem cells (MSCs) are the origin of bone-forming cells with immunomodulation potential. HLA-G5 is among the generated immunosuppressive molecules. HLA-G proteins play a crucial role in promoting the acceptance of allografts. However, the mechanisms regulating the expression of HLA-G5 in human MSCs are unknown. We induced differentiation of MSCs and found that HLA-G5 was greatly up-regulated only in osteoblastic cells (+63% for mRNA). Growth plates and bone callus postfracture in adults showed that only bone-lining cells and mesenchymal progenitors were positive for HLA-G5. Use of gene silencing and dominant-negative factors revealed that HLA-G5 depends on the expression and function of the skeletogenesis master genes RUNX2 and DLX5. In addition, HLA-G5 could directly inhibit osteoclastogenesis by acting on monocytes through SHP1. However, in mature osteoblasts, the expression of HLA-G5 protein was greatly suppressed whereas the proosteoclastogenic factor, RANKL, was concomitantly increased. Down-regulation of HLA-G5 expression during the maturation of osteoblasts was due to binding of the repressor GLI3, a signal transducer of the Hedgehog pathway, to the GLI binding element within the HLA-G promoter. Our findings show that mesenchymal progenitors and osteoblastic cells specifically express HLA-G5 during osteogenesis, with a key role in bone homeostasis.


Indian Hedgehog; mesenchymal stem cells; osteoblasts; osteoclasts; osteogenesis

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