Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States of America; Indiana Center for Musculoskeletal Health, Indianapolis, IN, United States of America.
Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile; Center for Exercise, Metabolism and Cancer CEMC2016, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Bone. 2020 May;134:115301. doi: 10.1016/j.bone.2020.115301. Epub 2020 Feb 26.
Non-traditional bisphosphonates, that is, bisphosphonates that do not inhibit osteoclast viability or function, were initially reported in the 1990s by Socrates Papapoulos' group. Originally designed to study the role of the R1 residue of aminobisphosphonates on bisphosphonate affinity for hydroxyapatite, these modified bisphosphonates retained similar affinity for mineralized bone as their parent compounds, but they lacked the potential to inhibit the mevalonate pathway or bone resorption. We found that, similar to classical bisphosphonates, these non-traditional compounds prevented osteoblast and osteocyte apoptosis in vitro through a pathway that requires the expression of the gap junction protein connexin 43, and the activation of the Src/MEK/ERK signaling pathway. Furthermore, one of those compounds named IG9402 (also known as amino-olpadronate or lidadronate), was able to inhibit osteoblast and osteocyte apoptosis, without affecting osteoclast number or bone resorption in vivo in a model of glucocorticoid-induced osteoporosis. IG9402 administration also ameliorated the decrease in bone mass and in bone mechanical properties induced by glucocorticoids. Similarly, IG9402 prevented apoptosis of osteoblastic cells in a model of immobilization due to hindlimb unloading. However, in this case, the bisphosphonate was not able to preserve the bone mass, and only partially prevented the decrease in bone mechanical properties induced by immobilization. The effect of IG9402 administration was also tested in a mouse model of masticatory hypofunction through the induction of masseter muscle atrophy by unilateral injection of botulinum toxin type A (BoNTA). IG9402 partially inhibited the loss of trabecular bone microstructure in the mandibular condyle, but not the decrease in masseter muscle mass induced by BoNTA administration. In summary, these non-traditional bisphosphonates that lack anti-resorptive activity but are able to preserve osteoblast and osteocyte viability could constitute useful tools to study the consequences of preventing apoptosis of osteoblastic cells in animal models. Furthermore, they could be used to treat conditions associated with reduced bone mass and increased bone fragility in which a reduction of bone remodeling is not desirable.
非传统双膦酸盐，即不抑制破骨细胞活力或功能的双膦酸盐，最初是由 Socrates Papapoulos 小组于 20 世纪 90 年代报道的。这些经过修饰的双膦酸盐最初设计用于研究氨基双膦酸盐的 R1 残基在双膦酸盐与羟磷灰石亲和力上的作用，它们与母体化合物相比对矿化骨具有相似的亲和力，但缺乏抑制甲羟戊酸途径或骨吸收的潜力。我们发现，与经典双膦酸盐类似，这些非传统化合物通过一种需要间隙连接蛋白连接蛋白 43 表达和Src/MEK/ERK 信号通路激活的途径，防止体外成骨细胞和破骨细胞凋亡。此外，其中一种名为 IG9402（也称为氨基奥帕膦酸盐或利达膦酸盐）的化合物能够抑制成骨细胞和破骨细胞凋亡，而不影响体内糖皮质激素诱导的骨质疏松模型中的破骨细胞数量或骨吸收。IG9402 给药还改善了糖皮质激素引起的骨量减少和骨力学性能下降。同样，IG9402 可防止因后肢去负荷引起的成骨细胞凋亡模型中的成骨细胞凋亡。然而，在这种情况下，双膦酸盐不能保留骨量，仅部分预防了因固定引起的骨力学性能下降。通过单侧注射肉毒毒素 A（BoNTA）诱导咬肌萎缩，在咀嚼功能减退的小鼠模型中也测试了 IG9402 给药的效果。IG9402 部分抑制了下颌髁小梁骨微观结构的丢失，但不能抑制 BoNTA 给药引起的咬肌质量减少。总之，这些缺乏抗吸收活性但能够维持成骨细胞和破骨细胞活力的非传统双膦酸盐可能成为研究在动物模型中防止成骨细胞凋亡后果的有用工具。此外，它们可用于治疗与骨量减少和骨脆性增加相关的疾病，在这些疾病中，减少骨重塑是不理想的。
