The Effect of Gabapentin-Lactam Hydroxamic Acid Derivatives on Ovine Osteoblast Proliferation and Phenotype: Perspectives for Tissue Engineering Application
Fabian Duttenhoefer, MD/Marc Anton Fuessinger, MD/Sieglinde Ahne, MD/Toshiyuki Oshima, DMD/Ralf Gutwald, MD, DDS/Rainer Schmelzeisen, MD, DDS/Sebastian Sauerbier, MD, DDS
Purpose: Modern bone tissue engineering associated with mesenchymal stem cells (MSCs) provides promising treatment alternatives for the loss of bone, one of the foremost challenges in oral and craniofacial surgery today. The effect of gabapentin-lactam (GBP-L) and its analogs on osteogenic differentiated MSCs has not yet been deciphered. Consequently, this study investigates the effect of novel trans-8-tertbutylgabapentin-lactam (trans-8-TB-GBP-L) hydroxamic acid derivatives on metabolism, proliferation, and physiologic mineralization characteristics of ovine osteoblast cells. Materials and Methods: Osteoblasts were extracted and prepared from sheep femoral heads and cultured in medium enriched with hydroxamic acid derivatives of trans-8-TB-GBP-L. The cell proliferation rate, cell metabolism, cell viability, and basic osteoblastic function were assessed. Results: After 3 and 5 days of incubation, no significant increase in DNA content was detected in any of 12 test groups versus the control group. However, after 8 days of incubation, a significant increase of DNA contents in the test groups containing nanomolar concentrations of trans-8-TB-GBP-L hydroxamic acid derivatives was found. No significant aberration in metabolic activity was detected when any of the test substances were applied. ALP displayed similar activity rates among the test groups and the control at all time points. Calcification of osteoblastic cells occurred solely when nanomolar concentrations were used. Conclusion: Trans-8-TB-GBP-L hydroxamic acid derivatives do not interfere with physiologic function and phenotype of ovine osteoblasts. However, when applied at nanomolar concentrations, the assessed GBP-L derivatives significantly increased the cell proliferation rate after 8 days of incubation, indicating a dose-response curve with the maximum peak at nanomolar concentration and a retarded drug response between 5 and 8 days.