Heino Terhi J, Alm Jessica J, Halkosaari Heikki J, Välimäki Ville-Valtteri
a Department of Cell Biology and Anatomy , Institute of Biomedicine, University of Turku ;
b Orthopaedic Research Unit, University of Turku , Turku ;
Acta Orthop. 2016 Aug;87(4):412-7. doi: 10.1080/17453674.2016.1188258. Epub 2016 May 19.
Background and purpose - Bisphosphonates are widely used in the treatment of bone loss, but they might also have positive effects on osteoblastic cells and bone formation. We evaluated the effect of in vivo zoledronic acid (ZA) treatment and possible concomitant effects of ZA and fracture on the ex vivo osteogenic capacity of rat mesenchymal stromal cells (MSCs). Methods - A closed femoral fracture model was used in adult female rats and ZA was administered as a single bolus or as weekly doses up to 8 weeks. Bone marrow MSCs were isolated and cultured for in vitro analyses. Fracture healing was evaluated by radiography, micro-computed tomography (μCT), and histology. Results - Both bolus and weekly ZA increased fracture-site bone mineral content and volume. MSCs from weekly ZA-treated animals showed increased ex vivo proliferative capacity, while no substantial effect on osteoblastic differentiation was observed. Fracture itself did not have any substantial effect on cell proliferation or differentiation at 8 weeks. Serum biochemical markers showed higher levels of bone formation in animals with fracture than in intact animals, while no difference in bone resorption was observed. Interestingly, ex vivo osteoblastic differentiation of MSCs was found to correlate with in vivo serum bone markers. Interpretation - Our data show that in vivo zoledronic acid treatment can influence ex vivo proliferation of MSCs, indicating that bisphosphonates can have sustainable effects on cells of the osteoblastic lineage. Further research is needed to investigate the mechanisms.
背景与目的——双膦酸盐广泛用于治疗骨质流失，但它们可能对成骨细胞和骨形成也有积极作用。我们评估了体内唑来膦酸（ZA）治疗的效果以及ZA与骨折对大鼠间充质基质细胞（MSCs）体外成骨能力可能产生的伴随影响。方法——在成年雌性大鼠中使用闭合性股骨骨折模型，ZA以单次推注或每周给药直至8周的方式给药。分离并培养骨髓间充质干细胞用于体外分析。通过X线摄影、微计算机断层扫描（μCT）和组织学评估骨折愈合情况。结果——单次推注和每周使用ZA均增加了骨折部位的骨矿物质含量和体积。来自每周接受ZA治疗动物的间充质干细胞显示出体外增殖能力增强，而未观察到对成骨细胞分化有实质性影响。在8周时，骨折本身对细胞增殖或分化没有任何实质性影响。血清生化标志物显示骨折动物的骨形成水平高于完整动物，而未观察到骨吸收有差异。有趣的是，发现间充质干细胞的体外成骨细胞分化与体内血清骨标志物相关。解读——我们的数据表明，体内唑来膦酸治疗可影响间充质干细胞的体外增殖，这表明双膦酸盐可对成骨细胞系细胞产生持续影响。需要进一步研究来探究其机制。
