Artikel
Low doses of proteasome inhibitor, bortezomib stimulates bone formation in nonmyelomatous bone invivo
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Autoren
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Seemun Ray
- Laboratory of Experimental Trauma Surgery, Justus-Liebig-University, Giessen, Germany
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Ulrich Thormann
- Department of Trauma Surgery, Hospital Giessen-Marburg GmbH, Justus-Liebig-University, Giessen, Germany
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Ursula Sommer
- Laboratory of Experimental Trauma Surgery, Justus-Liebig-University, Giessen, Germany
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Michael Gelinsky
- Institute of Physical Chemistry, Medical Faculty of Technische Universität Dresden, University Hospital Carl Gustav Carus, Dresden, Germany
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Thomas Hanke
- Institute of Materials Science, Technische Universität Dresden, Dresden, Germany
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Christian Heiss
- Department of Trauma Surgery, University Hospital Giessen-Marburg, Justus-Liebig-University, Giessen, Germany
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Reinhard Schnettler
- Department of Trauma Surgery, University Hospital Giessen-Marburg, Justus-Liebig-University, Giessen, Germany
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Volker Alt
- Department of Trauma Surgery, Hospital Giessen-Marburg GmbH, Justus-Liebig-University, Giessen, Germany
| Veröffentlicht: | 5. Oktober 2015 |
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Gliederung
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Objectives: Multiple Myeloma is associated with increased osteoclastogenesis and decreased osteoblastogenesis.Proteasome inhibitors like bortezomib, are clinical potent antimyeloma agent. Local delivery of biological active molecules via biomaterial composite implants to the site of the lesion has been shown to be beneficial for bone and implant-associated infections. In anticancer treatment local delivery of anticancer agents to the neoplasia via biomaterial carriers has never been reported before. The purpose of the current is to present the concepts and the first invivo results for proteasome inhibitor composite biomaterials for local delivery of bortezomib [b] to proliferative multiple myeloma bone lesions including concentration measurements at different anatomical regions in a rat model.
Methods: 80 female Sprague-Dawley rats were randomized into five different treatment groups(n=16/group):1)Empty (2)XG (3)XG100b (4)XG500b (5)XG2500b.A 2.5 mm drill hole was then created in the metaphysis of the left femur. It was then either filled with the mentioned substitutes or left empty(control). After 4 weeks femora were harvested followed by histological, histomorphometrical and immunohistochemical(BMP2,OPG,RANKL,ASMA,ED1) analysis. TOF-SIMS was used to assess the distribution of released bortezomib.
SPSS was used for statistical analysis. Mann-Whitney U with bonferroni correction was used. To avoid type I errors Games-Howell test was also performed. p<0.05= significant
Results and Conclusion: Histomorphometric analysis showed a statistically significant increased bone formation in the XG100b when compared to empty (p=0.019), XG(p=0.051), XG500b(p=0.049) and XG2500b(p=0.001), respectively. The increased bone formation in case of XG100b was associated to the significantly increased osteoblast surface over bone surface (Ob.S/ BS) when compared to empty (p=0.000), XG(p=0.046), XG500b(p=0.022) and XG500b(p=0.051) respectively. This was further confirmed by immunohistochemistry which revealed a significant increase in BMP2 and OPG/RANKL levels in XG100b group when compared to all the other groups (p=0.000).
Interestingly, the lowest osteoclast activity (Oc/ BS; p=0.002) was seen with the highest bortezomib concentration i.e. XG2500b. In addition it also exhibited a significantly increased inflammation zone area when compared to empty (p=0.000), XG(p=0.002), XG100b(p=0.001) and XG2500b(p=0.004) respectively. ED1 positive cells were also found to be the highest in the XG2500b group followed by the XG500b group(p=0.05), the least being in the XG100b and empty group (p=0.009) respectively. TOF-SIMS analysis also revealed traces of bortezomib only at the highest concentration (XG2500b).
Low doses of bortezomib promotes bone formation in nonmyelomatous bones by stimulating osteoblastogenesis. However, osteoclastogenesis was inhibited with the highest concentration of bortezomib. Optimal doses of bortezomib and maintenance of the shelf-life during the preliminary stages of new bone bone formation is beneficial.
