Osteolytic bone resorption in adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is caused by human T lymphotropic virus type 1 (HTLV-1). Patients with ATLL frequently develop humoral hypercalcemia of malignancy (HHM) resulting from increased osteoclastic bone resorption. Our goal was to investigate the mechanisms of ATLL-induced osteoclastic bone resorption. Murine calvaria co-cultured with HTLV-1-infected cells directly or conditioned media from cell cultures had increased osteoclast activity that was dependent on RANKL, indicating that factors secreted from ATLL cells had a stimulatory effect on bone resorption. Factors released from resorbing bone stimulated proliferation of HTLV-1-infected T-cells. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1alpha (MIP-1alpha), both osteoclast stimulators, were expressed in HTLV-1-infected T-cell lines. Interestingly, when HTLV-1-infected T-cells were co-cultured with pre-osteoblasts, the expression of osteoprotegerin (OPG), an osteoclast inhibitory factor, was significantly down-regulated in the pre-osteoblasts. When OPG was added into the ex vivo osteoclastogenesis assay induced by HTLV-1-infected T-cells, osteoclastogenesis was strongly inhibited. In addition, HTLV-1-infected T-cells inhibited expression of early osteoblast genes and induced late genes. These regulators will serve as future therapeutic targets for the treatments of HHM in ATLL.
Shu
Sherry T
ST
Department of Veterinary Biosciences, Arthur G. James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA.
Martin
Chelsea K
CK
Thudi
Nanda K
NK
Dirksen
Wessel P
WP
Rosol
Thomas J
TJ
D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D015490:HTLV-I Infections / Q000150:complications / Q000235:genetics / Q000473:pathology; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000150:complications* / Q000235:genetics / Q000473:pathology / Q000821:virology; D051379:Mice; D010014:Osteolysis / Q000150:complications / Q000235:genetics / Q000378:metabolism
D002118:Calcium