Prevention of glucocorticoid induced bone changes with beta-ecdysone

Authors

Weiwei Dai, Li Jiang, Yu-An Evan Lay, Haiyan Chen, Guoqin Jin, Hongliang Zhang, Alexander Kot, Robert O. Ritchie, Nancy E. Lane, Wei Yao

Abstract

Beta-ecdysone (βEcd) is a phytoecdysteroid found in the dry roots and seeds of the asteraceae and achyranthes plants, and is reported to increase osteogenesis in vitro. Since glucocorticoid (GC) excess is associated with a decrease in bone formation, the purpose of this study was to determine if treatment with βEcd could prevent GC-induced osteoporosis. Two-month-old male Swiss-Webster mice (n = 8–10/group) were randomized to either placebo or slow release prednisolone pellets (3.3 mg/kg/day) and treated with vehicle control or βEcd (0.5 mg/kg/day) for 21 days. GC treatment inhibited age-dependent trabecular gain and cortical bone expansion and this was accompanied by a 30–50% lower bone formation rate (BFR) at both the endosteal and periosteal surfaces. Mice treated with only βEcd significantly increased bone formation on the endosteal and periosteal bone surfaces, and increased cortical bone mass were their controls to compare to GC alone. Concurrent treatment of βEcd and GC completely prevented the GC-induced reduction in BFR, trabecular bone volume and partially prevented cortical bone loss. In vitro studies determined that βEcd prevented the GC increase in autophagy of the bone marrow stromal cells as well as in whole bone. In summary, βEcd prevented GC induced changes in bone formation, bone cell viability and bone mass. Additional studies are warranted of βEcd for the treatment of GC induced bone loss.

Link To Article

http://dx.doi.org/10.1016/j.bone.2015.01.001

Sensitivity and Specificity of Radiographic Methods for Predicting Insertion Torque of Dental Implants

Authors

Arthur Rodriguez Gonzalez Cortes, DDS, PhD, Hazem Eimar, DDS, MS, Jorge de Sá Barbosa, DDS, MS, Claudio Costa, DDS, PhD, Emiko Saito Arita, DDS, PhD, Faleh Tamimi, DDS, PhD

Abstract

Background: Subjective radiographic classifications of alveolar bone have been proposed and correlated with implant insertion torque (IT). The present diagnostic study aimed to identify quantitative bone features influencing IT, and to use these findings to develop an objective radiographic classification for predicting IT.

Methods: Demographics, panoramic radiographs (taken at the beginning of dental treatment) and cone beam computed tomographic scans (taken for implant surgical planning) of a total of 25 patients receiving 31 implants were analyzed. Bone samples retrieved from implant sites were assessed with dual x-ray absorptiometry, micro-computed tomography and histology. Odds ratio, sensitivity and specificity of all variables to predict high peak IT were assessed.

Results: A ridge cortical thickness greater than .75mm and a normal appearance of the inferior mandibular cortex were the most sensitive variables for predicting high peak IT (87.5% and 75%, respectively). A classification based on the combination of both variables presented high sensitivity (90.9%) and specificity (100%) for predicting IT.

Conclusion: Within the limitations of this study, the present results suggest that it is possible to predict IT accurately, based on radiographic findings of the patient. This could be useful in the treatment plan of immediate loading cases.

Link To Article

http://dx.doi.org/10.1902/jop.2015.140584

Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model

Authors

Laura E. Wright Ph.D., Jeroen T. Buijs Ph.D., Hun-Soo Kim M.D., Laura E. Coats M.D., Anne M. Scheidler M.D., Sutha K. John M.S., Yun She B.A., Sreemala Murthy M.S., Ning Ma M.D., Helen J. Chin- Sinex B.S., Teresita M. Bellido Ph.D., Ted A. Bateman Ph.D., Marc S. Mendonca Ph.D., Khalid S. Mohammad M.D., Ph.D. and Theresa A. Guise M.D.

Abstract

Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well characterized in clinically relevant animal models. Using twenty-week male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One-week post-irradiation, trabecular bone volume declined in irradiated tibiae (-22%; p < 0.0001) and femora (-14%; p = 0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibiae (-17%; p = 0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, while osteoblast number was unchanged. Despite no change in osteoblast number one-week post-irradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose- and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, while calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48h post-irradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation and co-culture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multi-faceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses and have important implications for bone health in patients treated with radiation therapy.

Link To Article

http://dx.doi.org/10.1002/jbmr.2458

Upregulation of BMP2/4 signaling increases both osteoblast-specific marker expression and bone marrow adipogenesis in Gja1Jrt/+ stromal cell cultures

Authors

Tanya Zappitelli, Frieda Chen, and Jane E. Aubin

Abstract

Gja1Jrt/+ mice carry a mutation in one allele of the gap junction protein, alpha 1 gene (Gja1), resulting in a G60S Connexin 43 (Cx43) mutant protein that is dominant negative for Cx43 protein production of <50% of wild type (WT) levels and significantly reduced gap junction formation and function in osteoblasts and other Cx43-expressing cells. Earlier we reported that Gja1Jrt/+ mice exhibited early-onset osteopenia caused by activation of osteoclasts secondary to activation of osteoblast lineage cells, which expressed increased RANKL and produced an abnormal resorption-stimulating bone matrix, high in BSP content. Gja1Jrt/+ mice also displayed early and progressive bone marrow atrophy, with a significant increase in bone marrow adiposity versus WT littermates but no increase in adipose tissues elsewhere in the body. BMP2/4 production and signaling were increased in Gja1Jrt/+ trabecular bone and osteogenic stromal cell cultures, which contributed to the upregulated expression of osteoblast-specific markers (e.g. Bsp and Ocn) in Gja1Jrt/+ osteoblasts and increased Pparg2 expression in bone marrow-derived adipoprogenitors in vitro. The elevated levels of BMP2/4 signaling in G60S Cx43-containing cells resulted at least in part from elevated levels of cAMP. We conclude that up-regulation of BMP2/4 signaling in trabecular bone and/or stromal cells increases osteoblast-specific marker expression in hyperactive Gja1Jrt/+ osteoblasts, and may also increase bone marrow adipogenesis by up-regulation of Pparg2 in the Cx43-deficient Gja1Jrt/+ mouse model.

Link To Article

http://dx.doi.org/10.1091/mbc.E14-06-1136

Deletion of Nrf2 Reduces Skeletal Mechanical Properties and Decreases Load-Driven Bone Formation

Authors

Yong-Xi, Lei Li, Kylie A. Corry, Pei Zhang, Yang Yang, Evan Himes, Cristina Layla Mihuti, Cecilia Nelson, Guoli Dai, Jiliang Li

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. The aim of this study was to investigate the role of Nrf2 in load-driven bone metabolism using Nrf2 knockout (KO) mice. Compared to age-matched littermate wild-type controls, Nrf2 KO mice have significantly lowered femoral bone mineral density (-7%, p < 0.05), bone formation rate (-40%, p < 0.05), as well as ultimate force (-11%, p < 0.01). The ulna loading experiment showed that Nrf2 KO mice were less responsive than littermate controls, as indicated by reduction in relative mineralizing surface (rMS/BS, -69%, p < 0.01) and relative bone formation rate (rBFR/BS, -84%, p < 0.01). Furthermore, deletion of Nrf2 suppressed load-driven gene expression of antioxidant enzymes and Wnt5a in cultured primary osteoblasts. Taken together, the results suggest that the loss-of-function mutation of Nrf2 in bone impairs bone metabolism and diminishes load-driven bone formation.

Link To Article

http://dx.doi.org/10.1016/j.bone.2014.12.066

A BIODEGRADABLE GENTAMICIN-HYDROXYAPATITE-COATING FOR INFECTION PROPHYLAXIS IN CEMENTLESS HIP PROSTHESES

Authors

D. Neut, R.J.B. Dijkstra, J.I. Thompson, C. Kavanagh, H.C. van der Mei and H.J. Busscher

Abstract

A degradable, poly (lactic-co-glycolic acid) (PLGA), gentamicin-loaded prophylactic coating for hydroxyapatite (HA)-coated cementless hip prostheses is developed with similar antibacterial efficacy as offered by gentamicinloaded cements for fixing traditional, cemented prostheses in bone. We describe the development pathway, from in vitro investigation of antibiotic release and antibacterial properties of this PLGA-gentamicin-HA-coating in different in vitro models to an evaluation of its efficacy in preventing implant-related infection in rabbits. Bone in-growth in the absence and presence of the coating was investigated in a canine model. The PLGAgentamicin-HA-coating showed high-burst release, with antibacterial efficacy in agar-assays completely disappearing after 4 days, minimising risk of inducing antibiotic resistance. Gentamicin-sensitive and gentamicinresistant staphylococci were killed by the antibiotic-loaded

coating, in a simulated prosthesis-related interfacial gap. PLGA-gentamicin-HA-coatings prevented growth of bioluminescent staphylococci around a miniature-stem mounted in bacterially contaminated agar, as observed using bio-optical imaging. PLGA-gentamicin-HA-coated pins inserted in bacterially contaminated medullary canals in rabbits caused a statistically significant reduction in infection rates compared to HA-coated pins without gentamicin. Bone ingrowth to PLGA-gentamicin-HA coated pins, in condylar defects of Beagle dogs was not

impaired by the presence of the degradable, gentamicin loaded coating. In conclusion, the PLGA-gentamicin HA-coating constitutes an effective strategy for infection prophylaxis in cementless prostheses.

Link to Article

http://www.ecmjournal.org/journal/papers/vol029/pdf/v029a04.pdf