title: Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease.
abstract: Interleukin 8 (IL-8) is a member of the alpha chemokine family of cytokines originally identified as a neutrophil chemoattractant. Recently, we reported that elevated levels of IL-8, but not parathyroid hormone-related protein (PTHrP), correlated with increased bone metastasis in a population of human breast cancer cells. We hypothesized that IL-8 expression by breast cancer cells would either indirectly influence osteoclastogenesis via nearby stromal cells or directly influence osteoclast differentiation and activity. In the present study, we investigated the role of IL-8 in the process of osteoclast formation and bone resorption, which is associated with metastatic breast cancer. The addition of recombinant human (rh) IL-8 (10 ng/ml) to cultures of stromal osteoblastic cells stimulated both RANKL mRNA expression and protein production, with no effect on the expression of osteoprotegerin. In addition, rhIL-8 also directly stimulated the differentiation of human peripheral blood mononuclear cells into bone-resorbing osteoclasts. In these cultures, IL-8 was able to stimulate human osteoclast formation even in the presence of excess (200 ng/ml) RANK-Fc. The effect of IL-8 on osteoclasts and their progenitors was associated with the cell surface expression of the IL-8-specific receptor (CXCR1) on the cells. These results demonstrate a direct effect of IL-8 on osteoclast differentiation and activity. Together, these data implicate IL-8 in the osteolysis associated with metastatic breast cancer.
authors.affiliation: Center for Orthopaedic Research, Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Manali S
authors.initials: MS
authors.lastname: Bendre
authors.forename: Donna C
authors.initials: DC
authors.lastname: Montague
authors.forename: Terry
authors.initials: T
authors.lastname: Peery
authors.forename: Nisreen S
authors.initials: NS
authors.lastname: Akel
authors.forename: Dana
authors.initials: D
authors.lastname: Gaddy
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D001862:Bone Resorption / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010014:Osteolysis / Q000473:pathology*; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; D016209:Interleukin-8; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse