title: The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro.
abstract: Previous studies have attributed the increase in bone mass observed following bisphophonate (BP) therapy to their effects on bone-resorbing osteoclasts (OCs). However, recent evidence suggests that BPs can also act directly on bone forming osteoblasts (OBs) to increase their anabolic activity. Using an established model of in vitro OB differentiation, we found that the potent nitrogen-containing BP, zoledronic acid (ZOL), may enhance the bone forming potential of human adult OB-like cells in vitro by inducing their differentiation. ZOL dose dependently induced both cytostasis and cell death in OB-like cells at concentrations of 0.5 microM or greater. Cells expressing high levels of the osteoprogenitor antigen, STRO-1, exhibited a greater proliferative potential than STRO-1negative/dim cells, and were more susceptible to the cytostatic and apoptotic effects of ZOL. ZOL was also found to promote bone cell differentiation, as evidenced by an increase in the number of cells exhibiting a more differentiated (STRO-1(-)/AP+ and STRO-1(-)/AP-) phenotype. Analysis of gene expression, using semi-quantitative RT-PCR, demonstrated that ZOL treatment resulted in a significant upregulation of osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2) gene expression. Furthermore, in vitro mineralisation studies revealed that ZOL enhanced mineralised matrix formation at concentrations between 5 and 25 microM. These results show that, in addition to its direct effects on OCs, ZOL also directly affects the proliferation and differentiation of human OB-like cells in vitro and may enhance bone formation in vivo.
authors.affiliation: Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory, Division of Haematology, Institute of Medical and Veterinary Science, Adelaide 5000, Australia.
authors.forename: Beiqing
authors.initials: B
authors.lastname: Pan
authors.forename: Luen Bik
authors.initials: LB
authors.lastname: To
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Farrugia
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Jonathan
authors.initials: J
authors.lastname: Green
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
authors.forename: Kevin
authors.initials: K
authors.lastname: Lynch
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
mesh_terms: D002113:Calcification, Physiologic / Q000187:drug effects*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D009584:Nitrogen / Q000737:chemistry*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D009584:Nitrogen