T Cell Activation Induces Human Osteoclast Formation via Receptor Activator of Nuclear Factor κB Ligand-Dependent and -Independent Mechanisms

Authors

  • M. Neale Weitzmann,

    1. Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, USA
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    • These authors contributed equally to this work.

  • Simone Cenci,

    1. Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, USA
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    • These authors contributed equally to this work.

  • Leonard Rifas,

    1. Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, USA
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  • Jeffrey Haug,

    1. Division of Bone Marrow Transplant and Stem Cell Biology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, USA
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  • John Dipersio,

    1. Division of Bone Marrow Transplant and Stem Cell Biology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, USA
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  • Roberto Pacifici

    Corresponding author
    1. Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, USA
    • Roberto Pacifici, M.D. Division of Bone and Mineral Diseases Barnes-Jewish Hospital-North 216 South Kingshighway Boulevard St. Louis, MO 63110, USA
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Abstract

In unstimulated conditions, osteoclast (OC) formation is regulated by stromal cell production of the key osteoclastogenic factors receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). However, the mechanisms of accelerated osteoclastogenesis and bone loss characteristic of inflammatory conditions are poorly understood but appear to involve T cells. In addition, the mechanism by which OCs arise spontaneously in cultures of peripheral blood mononuclear cells in the absence of stromal cells or added cytokines remains unclear. Using a stromal cell free human osteoclast generating system, we investigated the ability of activated T cells to support osteoclastogenesis. We show that when activated by phytohemagglutinin-P (PHA), T cells (both CD4+ and CD8+) stimulate human OC formation in vitro. Although both soluble M-CSF and RANKL were detected in activated T cell supernatants, the presence of M-CSF was not essential for macrophage survival or RANKL-dependent osteoclast formation, suggesting that other soluble T cell-derived factors were capable of substituting for this cytokine. We also found that saturating concentrations of osteoprotegerin (OPG) failed to neutralize 30% of the observed OC formation and that T cell conditioned medium (CM) could superinduce osteoclastogenesis in cultures of purified monocytes maximally stimulated by RANKL and M-CSF. Together, these data suggest that activated T cells support osteoclastogenesis via RANKL-dependent and -independent mechanisms. Although not relevant for T cell-induced osteoclastogenesis, secretion of soluble M-CSF is a previously undescribed property of activated T cells.

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