title: Override of the osteoclast defect in osteopontin-deficient mice by metastatic tumor growth in the bone.
abstract: Osteopontin (OPN) is a major noncollagenous protein of bone that is frequently up-regulated in tumors, where it enhances tumor growth. OPN-deficient mice are resistant to stimulated bone resorption, including that occurring after ovariectomy. Using a new syngeneic model of bone metastasis (r3T), we examined whether OPN-deficient mice are similarly resistant to bone loss resulting from osteolytic tumor growth. Transformed mammary epithelial cells, r3T, which express parathyroid hormone-related protein but not receptor activator of nuclear factor-kappaB ligand, were injected via the intracardiac route into both wild-type and OPN-/- mice. We measured tumor burden in the bone by quantitative polymerase chain reaction assay and evaluated bone loss by X-ray and microCT. Unexpectedly, bone loss was similar in OPN-/- and wild-type mice bearing similar-sized tumors. Osteoclast number was comparable in both genotypes, and the expression of bone sialoprotein was similar in tumor-bearing bones of both genotypes, excluding two potential mechanisms of overriding the defect. Taken together, these results indicate that in the absence of OPN, the bone loss associated with tumor growth at the bone site proceeds rapidly despite the osteoclast defects documented in OPN-/- mice, suggesting that the mechanism of bone loss due to tumor growth differs from that occurring in other pathologies.
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Tajneen
authors.initials: T
authors.lastname: Natasha
authors.forename: Misty
authors.initials: M
authors.lastname: Kuhn
authors.forename: Owen
authors.initials: O
authors.lastname: Kelly
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rittling
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D058574:Integrin-Binding Sialoprotein; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010010:Osteoclasts / Q000473:pathology*; D053495:Osteopontin; D010024:Osteoporosis / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D044162:Parathyroid Hormone-Related Protein; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D015127:9,10-Dimethyl-1,2-benzanthracene