1Institute for Hard Tissue and Bio-tooth Regeneration (IHBR), Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940 Republic of Korea.
2Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940 Republic of Korea.
Tissue Eng Regen Med. 2019 Apr 2;16(3):265-273. doi: 10.1007/s13770-019-00186-y. eCollection 2019 Jun.
Wear debris-induced osteolysis leads to periprosthetic loosening and subsequent prosthetic failure. Since excessive osteoclast formation is closely implicated in periprosthetic osteolysis, identification of agents to suppress osteoclast formation and/or function is crucial for the treatment and prevention of wear particle-induced bone destruction. In this study, we examined the potential effect of pentamidine treatment on titanium (Ti) particle-induced osteolysis, and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis.
The effect of pentamidine treatment on bone destruction was examined in Ti particle-induced osteolysis mouse model. Ti particles were implanted onto mouse calvaria, and vehicle or pentamidine was administered for 10 days. Then, calvarial bone tissue was analyzed using micro-computed tomography and histology. We performed osteoclastogenesis assay using bone marrow-derived macrophages (BMMs) to determine the effect of pentamidine on osteoclast formation. BMMs were treated with 20 ng/mL RANKL and 10 ng/mL macrophage colony-stimulating factor in the presence or absence of pentamidine. Osteoclast differentiation was determined by tartrate-resistant acid phosphatase staining, real-time polymerase chain reaction, and immunofluorescence staining.
Pentamidine administration decreased Ti particle-induced osteoclast formation significantly and prevented bone destruction compared to the Ti particle group . Pentamidine also suppressed RANKL-induced osteoclast differentiation and actin ring formation markedly, and inhibited the expression of nuclear factor of activated T cell c1 and osteoclast-specific genes . Additionally, pentamidine also attenuated RANKL-mediated phosphorylation of IκBα in BMMs.
These results indicate that pentamidine is effective in inhibiting osteoclast formation and significantly attenuates wear debris-induced bone loss in mice.
磨损颗粒诱导的骨溶解导致假体松动和随后的假体失败。由于破骨细胞的过度形成与假体周围骨溶解密切相关，因此鉴定抑制破骨细胞形成和/或功能的药物对于治疗和预防磨损颗粒诱导的骨破坏至关重要。在这项研究中，我们研究了戊二脒治疗对钛（Ti）颗粒诱导的骨溶解和核因子-κB 配体（RANKL）诱导的破骨细胞形成的潜在影响。
在 Ti 颗粒诱导的骨溶解小鼠模型中研究了戊二脒治疗对骨破坏的影响。将 Ti 颗粒植入小鼠颅骨，给予载体或戊二脒 10 天。然后，通过微计算机断层扫描和组织学分析颅骨骨组织。我们使用骨髓来源的巨噬细胞（BMM）进行破骨细胞形成测定，以确定戊二脒对破骨细胞形成的影响。BMM 用 20ng/mL RANKL 和 10ng/mL 巨噬细胞集落刺激因子处理，存在或不存在戊二脒。通过抗酒石酸酸性磷酸酶染色、实时聚合酶链反应和免疫荧光染色来确定破骨细胞分化。
与 Ti 颗粒组相比，戊二脒给药显著减少了 Ti 颗粒诱导的破骨细胞形成，并防止了骨破坏。戊二脒还显著抑制了 RANKL 诱导的破骨细胞分化和细胞环形成，并抑制了核因子活化 T 细胞 c1 和破骨细胞特异性基因的表达。此外，戊二脒还减弱了 RANKL 介导的 BMMs 中 IκBα的磷酸化。
这些结果表明，戊二脒能有效抑制破骨细胞形成，并显著减轻小鼠磨损颗粒诱导的骨丢失。
