title: Inflammatory T cells rapidly induce differentiation of human bone marrow stromal cells into mature osteoblasts.
abstract: Activated T cells secrete multiple osteoclastogenic cytokines which play a major role in the bone destruction associated with rheumatoid arthritis. While the role of T cells in osteoclastogenesis has received much attention recently, the effect of T cells on osteoblast formation and activity is poorly defined. In this study, we investigated the hypothesis that in chronic inflammation activated T cells contribute to enhanced bone turnover by promoting osteoblastic differentiation. We show that T cells produce soluble factors that induce alkaline phosphatase activity in bone marrow stromal cells and elevated expression of mRNA for Runx2 and osteocalcin. This data indicate that T cell derived factors have the capacity to stimulate the differentiation of bone marrow stromal cells into the osteoblast phenotype. RANKL mRNA was undetectable under any conditions in highly purified bone marrow stromal cells. In contrast, RANKL was constitutively expressed in primary osteoblasts and only moderately up-regulated by activated T cell conditioned medium. Interestingly, both bone marrow stromal cells and osteoblasts expressed mRNA for RANK, which was strongly up-regulated in both cell types by activated T cell conditioned medium. Although, mRNA for the RANKL decoy receptor, osteoprotegerin, was also up-regulated by activated T cell conditioned medium, it's inhibitory effects may be mitigated by a simultaneous rise in the osteoprotegerin competitor TNF-related apoptosis-inducing ligand. Based on our data we propose that during chronic inflammation, T cells regulate bone loss by a dual mechanism involving both direct stimulation of osteoclastogenesis, by production of osteoclastogenic cytokines, and indirectly by induction of osteoblast differentiation and up-regulation of bone turnover via coupling.
authors.affiliation: Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA. lrifas@imgate.wustl.edu
authors.forename: Leonard
authors.initials: L
authors.lastname: Rifas
authors.forename: Sophia
authors.initials: S
authors.lastname: Arackal
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis / Q000096:biosynthesis; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D001862:Bone Resorption / Q000503:physiopathology / Q000517:prevention & control; D002352:Carrier Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin / Q000096:biosynthesis; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor; D017154:Stromal Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned; D016207:Cytokines; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D015675:Osteocalcin; D000469:Alkaline Phosphatase