Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line

• Published in: British journal of cancer Vol. 84; no. 7; pp. 951 - 958
• Main Authors: MACKIE, P. S, FISHER, J. L, ZHOU, H, CHOONG, P. F. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 06.04.2001
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Bisphosphonates; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell culture; Cell Division - drug effects; Cell growth; Clodronic Acid - pharmacology; Diphosphonates - pharmacology; Dose-Response Relationship, Drug; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Glycoproteins - biosynthesis; Glycoproteins - genetics; Growth Inhibitors - pharmacology; Medical research; Medical sciences; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Metastasis; Osteoprotegerin; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - pathology; Pharmacology. Drug treatments; Prostate cancer; RANK Ligand; Rats; Receptors, Cytoplasmic and Nuclear - biosynthesis; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Tumor Necrosis Factor; Regular; Tumor Cells, Cultured; Australia; Antineoplastic agent; Cell proliferation; Rat; Ligand; Diseases of the osteoarticular system; Diphosphonic acid derivatives; Bisphosphonates; Dose activity relation; Activator; Osteosarcoma; Established cell line; Genetics; Inhibition; Transcription factor NFκB; Biological receptor; Rodentia; Osteopontin; Time response relation; Malignant tumor; Gene expression; In vitro; Pamidronic acid; Biological activity; Clodronic acid; Vertebrata; Mammalia; Cell death; Animal; Bone; Apoptosis
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1054/bjoc.2000.1679

Local growth of osteosarcoma involves destruction of host bone by proteolytic mechanisms and/or host osteoclast activation. Osteoclast formation and activity are regulated by osteoblast-derived factors such as the osteoclast differentiating factor, receptor activator of NF-kappaB ligand (RANKL) and the inhibitor osteoprotegerin (OPG). We have investigated the in vitro effects of bisphosphonates on a clonal rat osteosarcoma cell line. The aminobisphosphonate pamidronate was added to UMR 106-01 cell cultures (10(-8)M to 10(-4)M up to 5 days). The non-aminobisphosphonate clodronate was administered for the same time periods (10(-6)M to 10(-2)M). Cell proliferation, apoptosis and mRNA expression was assessed. Both agents inhibited cell proliferation in a time- and dose-dependent manner. ELISA analysis demonstrated an increase in DNA fragmentation although there was no significant dose-related difference between the doses studied. Bisphosphonate-treated cultures had a greater subpopulation of cells exhibiting morphological changes of apoptosis. Expression of mRNA for osteopontin and RANKL was down-regulated by both agents, while the expression of mRNA for alkaline phosphatase, pro-alpha1(I) collagen and OPG was not altered. Out in vitro work suggests the bisphosphonates not only have direct effects on osteosarcoma cell growth and apoptosis, but also, by altering the relative expression of osteoclast-regulating factors, they may inhibit the activity of osteoclasts and their recruitment.