Browsing by Author "Brown, Drew"

Now showing 1 - 4 of 4
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    Compromised vertebral structural and mechanical properties associated with progressive kidney disease and the effects of traditional pharmacological interventions
    (Elsevier, 2015-08) Newman, Christopher L.; Chen, Neal X.; Smith, Eric; Smith, Mark; Brown, Drew; Moe, Sharon M.; Allen, Matthew R.; Department of Anatomy & Cell Biology, IU School of Medicine
    BACKGROUND/AIMS: Patients with chronic kidney disease mineral and bone disorder (CKD-MBD) have a significantly higher vertebral and non-vertebral fracture risk than the general population. Several preclinical models have documented altered skeletal properties in long bones, but few data exist for vertebral bone. The goal of this study was to examine the effects of progressive CKD on vertebral bone structure and mechanics and to determine the effects of treatment with either bisphosphonates or anti-sclerostin antibody in groups of animals with high or low PTH. METHODS: Animals with progressive kidney disease were left untreated, treated with calcium to lower PTH, zoledronic acid to lower remodeling without affecting PTH, anti-sclerostin antibody, or anti-sclerostin antibody plus calcium. Non-diseased, untreated littermates served as controls. Vertebral bone morphology (trabecular and cortical) and mechanical properties (structural and material-level) were assessed at 35 weeks of age by microCT and mechanical testing, respectively. RESULTS: CKD with high PTH resulted in 6-fold higher bone formation rate, significant reductions in the amount of trabecular and cortical bone, and compromised whole bone mechanical properties in the vertebra compared to normal animals. Treatments that reduced bone remodeling were effective in normalizing vertebral structure and mechanical properties only if the treatment reduced serum PTH. Similarly, treatment with anti-sclerostin antibody was effective in enhancing bone mass and mechanical properties but only if combined with PTH-suppressive treatment. CONCLUSIONS: CKD significantly altered both cortical and trabecular bone properties in the vertebra resulting in compromised mechanical properties and these changes can be normalized by interventions that involve reductions in PTH levels.
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    Kalirin Decreases Bone Mass Through Effects in Both Osteoclasts and Osteoblasts
    (Office of the Vice Chancellor for Research, 2012-04-13) Huang, Su; Eleniste, Pierre; LeBlanc, Paula; Brown, Drew; Allen, Matthew R.; Bruzzaniti, Angela
    Bone homeostasis is maintained by the balance between osteoclasts which degrade bone and osteoblasts, which form new bone. When the activity of either of these cells is dysregulated, bone loss can ensue, leading to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. The activity of osteoclasts and osteoblasts is regulated by local and systemic factors, as well as by key signaling proteins expressed in these cells. Kalirin is a novel GTP-exchange factor protein that plays a role in signaling pathways leading to cytoskeletal remodeling and dendritic spine formation in neurons, but its function in other cells is unknown. Western blotting and real time PCR confirmed that Kalirin is expressed in osteoclasts and osteoblasts, suggesting it may play a role in regulating bone cell function and bone mass. We used micro-CT to examine the bone phenotype of 14 week old female mice lacking Kalirin in all tissues (Kal-KO). Kal-KO mice exhibited a 40% lower trabecular bone volume in the distal femur compared to wild-type (WT) mice (n=9/group, p<0.05). We next quantified osteoclasts in histological sections by counting multinucleated cells expressing tartrate-resistant acid phosphatase (TRAP), a marker of mature osteoclasts. We found 48% higher osteoclast surface/bone surface in trabecular bone of Kal-KO mice, compared to WT mice (n=6/group, p<0.05). Osteoclast differentiation is controlled by osteoblasts, which secrete receptor activator of NF-kB ligand (RANKL), macrophage colony stimulating factor (MCSF) and osteoprotegerin (OPG), a decoy receptor for RANKL. We examined if Kalirin could regulate osteoclast differentiation in vitro. Osteoclasts were generated from the bone marrow of WT or Kal-KO mice by incubation with RANKL and MCSF for 7 days, and TRAP+ multinucleated cells were counted. Consistent with our in vivo studies, osteoclast number was significantly higher in cultures from Kal-KO mice, compared to WT mice. We next examined if Kalirin altered the ratio of secreted RANKL and OPG secreted by osteoblasts. Osteoblasts were generated from the calvaria of 2 day old neonates and the level of secreted RANKL and OPG in conditioned media was quantified by ELISA. Consistent with increased osteoclast differentiation, we found a higher RANKL/OPG ratio in conditioned media from Kal-KO osteoblasts, compared to WT cells. These data confirm a role for Kalirin in the regulation of trabecular bone mass through effects in both osteoclasts and osteoblasts.
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    Raloxifene improves bone mechanical properties in mice previously treated with zoledronate
    (SpringerLink, 2017-07) Meixner, Cory N.; Aref, Mohammad W.; Gupta, Aryaman; McNerny, Erin M.B.; Brown, Drew; Wallace, Joseph M.; Allen, Matthew R.; Anatomy and Cell Biology, School of Medicine
    Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.
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    Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes
    (Springer, 2016-12) Aref, Mohammad W.; McNerny, Erin M.B.; Brown, Drew; Jepsen, Karl J.; Allen, Matthew R.; Anatomy and Cell Biology, School of Medicine
    Aref, M. W., McNerny, E. M. B., Brown, D., Jepsen, K. J., & Allen, M. R. (2016). Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes. Osteoporosis International : A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 27(12), 3637–3643. https://doi.org/10.1007/s00198-016-3701-9