title: The ARF tumor suppressor regulates bone remodeling and osteosarcoma development in mice.
abstract: The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf(-/-) mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf(-/-) mice had increased expression of OB genes while Arf(-/-) OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf(-/-) mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf(-/-) tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf(+/-) mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf(-/-) mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS.
authors.affiliation: Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Rauch
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Hurchla
authors.forename: John C
authors.initials: JC
authors.lastname: Harding
authors.forename: Hongju
authors.initials: H
authors.lastname: Deng
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Shea
authors.forename: Mark C
authors.initials: MC
authors.lastname: Eagleton
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lairmore
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Jason D
authors.initials: JD
authors.lastname: Weber
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D002277:Carcinoma / Q000235:genetics*; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology; D016356:Gene Products, tax / Q000235:genetics*; D016158:Genes, p53; D006579:Heterozygote; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D010006:Osteoblasts / Q000166:cytology*; D010010:Osteoclasts / Q000166:cytology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D016356:Gene Products, tax; D007093:Imidazoles; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D000077211:Zoledronic Acid