title: Regulation and function of immunosuppressive molecule human leukocyte antigen G5 in human bone tissue.
abstract: 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.
authors.affiliation: Stromalab 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.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Deschaseaux
authors.forename: Julien
authors.initials: J
authors.lastname: Gaillard
authors.forename: Alain
authors.initials: A
authors.lastname: Langonné
authors.forename: Christophe
authors.initials: C
authors.lastname: Chauveau
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Naji
authors.forename: Amina
authors.initials: A
authors.lastname: Bouacida
authors.forename: Philippe
authors.initials: P
authors.lastname: Rosset
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Gonzague
authors.initials: G
authors.lastname: De Pinieux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouas-Freiss
authors.forename: Luc
authors.initials: L
authors.lastname: Sensébé
mesh_terms: D000328:Adult; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D059951:HLA-G Antigens / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C100596:DLX5 protein, human; D059951:HLA-G Antigens; D018398:Homeodomain Proteins; C493709:RUNX2 protein, human; D014157:Transcription Factors
keywords: Indian Hedgehog; mesenchymal stem cells; osteoblasts; osteoclasts; osteogenesis