title: Transglutaminases factor XIII-A and TG2 regulate resorption, adipogenesis and plasma fibronectin homeostasis in bone and bone marrow.
abstract: Appropriate bone mass is maintained by bone-forming osteoblast and bone-resorbing osteoclasts. Mesenchymal stem cell (MSC) lineage cells control osteoclastogenesis via expression of RANKL and OPG (receptor activator of nuclear factor κB ligand and osteoprotegerin), which promote and inhibit bone resorption, respectively. Protein crosslinking enzymes transglutaminase 2 (TG2) and Factor XIII-A (FXIII-A) have been linked to activity of myeloid and MSC lineage cells; however, in vivo evidence has been lacking to support their function. In this study, we show in mice that TG2 and FXIII-A control monocyte-macrophage cell differentiation into osteoclasts as well as RANKL production in MSCs and in adipocytes. Long bones of mice lacking TG2 and FXIII-A transglutaminases, show compromised biomechanical properties and trabecular bone loss in axial and appendicular skeleton. This was caused by increased osteoclastogenesis, a cellular phenotype that persists in vitro. The increased potential of TG2 and FXIII-A deficient monocytes to form osteoclasts was reversed by chemical inhibition of TG activity, which revealed the presence of TG1 in osteoclasts and assigned different roles for the TGs as regulators of osteoclastogenesis. TG2- and FXIII-A-deficient mice had normal osteoblast activity, but increased bone marrow adipogenesis, MSCs lacking TG2 and FXIII-A showed high adipogenic potential and significantly increased RANKL expression as well as upregulated TG1 expression. Chemical inhibition of TG activity in the null cells further increased adipogenic potential and RANKL production. Altered differentiation of TG2 and FXIII-A null MSCs was associated with plasma fibronectin (FN) assembly defect in cultures and FN retention in serum and marrow in vivo instead of assembly into bone. Our findings provide new functions for TG2, FXIII-A and TG1 in bone cells and identify them as novel regulators of bone mass, plasma FN homeostasis, RANKL production and myeloid and MSC cell differentiation.
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.
authors.forename: Aisha
authors.initials: A
authors.lastname: Mousa
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.
authors.forename: Cui
authors.identifier: 0000-0002-4138-6830
authors.initials: C
authors.lastname: Cui
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.
authors.forename: Aimei
authors.initials: A
authors.lastname: Song
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.
authors.forename: Vamsee D
authors.initials: VD
authors.lastname: Myneni
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.
authors.forename: Huifang
authors.initials: H
authors.lastname: Sun
authors.affiliation: Shriners Hospital for Children, Montreal, QC, Canada.
authors.forename: Jin Jin
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.|Shriners Hospital for Children, Montreal, QC, Canada.
authors.forename: Monzur
authors.initials: M
authors.lastname: Murshed
authors.affiliation: Department Experimental Medicine & Surgery, University of Rome Tor Vergata, Rome, Italy.|MRC Toxicology Unit, Leicester LE19HN, UK.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, QC, Canada.|Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Mari T
authors.initials: MT
authors.lastname: Kaartinen
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D026122:Factor XIIIa / Q000235:genetics* / Q000378:metabolism; D005353:Fibronectins / Q000097:blood / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D005353:Fibronectins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D026122:Factor XIIIa; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C105804:transglutaminase 1; D019204:GTP-Binding Proteins