title: Sustained autocrine induction and impaired negative feedback of osteoclastogenesis in CD14(+) cells of giant cell tumor of bone.
abstract: Giant cell tumor (GCT) of bone is a histologically benign osteolytic tumor featuring prominent osteoclast-like giant cells, mononuclear osteoclast precursors, and spindle-shaped stromal cells (SCs). Thus far, most studies have identified SCs as truly transformed elements that are responsible for sustained giant cell formation via receptor activator of NF-κB ligand (RANKL) paracrine induction. However, we have previously shown that SCs are hyperplastic, rather than neoplastic, and able to induce giant cell formation similar to that of normal mesenchymal SCs; we hypothesized that other cell subsets of GCTs might be primarily relevant for the pathogenesis. In this study, we show that the nonproliferating CD14(+) cells of GCTs, exhibiting typical monoblast lineage features, secrete high amounts of RANKL, thereby activating a RANKL/RANK autocrine loop that determines sustained giant cell formation. Moreover, these cells also lack adequate negative feedback control of the RANKL signaling pathway, as determined by endogenous interferon β. These data demonstrate that CD14(+) cells of GCTs are abnormally stimulated to limitless differentiation into multinucleated giant cells and provide useful suggestions for the development of novel therapies.
authors: Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy. sofia.avnet@ior.it
authors: Sofia
authors: S
authors: Avnet
authors: Manuela
authors: M
authors: Salerno
authors: Nicoletta
authors: N
authors: Zini
authors: Marco
authors: M
authors: Alberghini
authors: Davide
authors: D
authors: Gibellini
authors: Nicola
authors: N
authors: Baldini
mesh_terms: D019898:Autocrine Communication; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D018212:Giant Cell Tumor of Bone / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008954:Models, Biological; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010012:Osteogenesis; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018950:Lipopolysaccharide Receptors; D053245:RANK Ligand; D012333:RNA, Messenger; D016899:Interferon-beta; D016173:Macrophage Colony-Stimulating Factor