IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
Vita-Salute San Raffaele University, Milan, Italy.
Geroscience. 2021 Apr;43(2):927-940. doi: 10.1007/s11357-020-00267-0. Epub 2020 Sep 30.
After middle age, in human bone, the resorption usually exceeds formation resulting in bone loss and increased risk of fractures in the aged population. Only few in vivo models in higher vertebrates are available for pathogenic and therapeutic studies about bone aging. Among these, male Danio rerio (zebrafish) can be successfully used as low vertebrate model to study degenerative alterations that affect the skeleton during aging, reducing the role of sex hormones.In this paper, we investigated the early bone aging mechanisms in male zebrafish (3, 6, 9 months old) scales evaluating the physiological changes and the effects of prednisolone, a pro-osteoporotic drug.The results evidentiated an age-dependent reduction of the mineralization rate in the fish scales, as highlighted by growing circle measurements. Indeed, the osteoblastic ALP activity at the matrix deposition site was found progressively downregulated.The higher TRAP activity was found in 63% of 9-month-old fish scales associated with resorption lacunae along the scale border. Gene expression analysis evidentiated that an increase of the tnfrsf1b (homolog of human rank) in aging scales may be responsible for resorption stimulation.Interestingly, prednisolone inhibited the physiological growth of the scale and induced in aged scales a more significant bone resorption compared with untreated fish (3.8% vs 1.02%). Bone markers analysis shown a significant reduction of ALP/TRAP ratio due to a prednisolone-dependent stimulation of tnfsf11 (homolog of human rankl) in scales of older fish.The results evidentiated for the first time the presence of a senile male osteoporosis in lower vertebrate. This new model could be helpful to identify the early mechanisms of bone aging and new therapeutic strategies to prevent age-related bone alterations in humans.
人到中年后，在骨骼中，吸收通常超过形成，导致骨质流失，老年人群骨折风险增加。仅有少数高等脊椎动物的体内模型可用于骨老化的发病机制和治疗研究。在这些模型中，雄性 Danio rerio（斑马鱼）可作为低等脊椎动物模型成功用于研究影响衰老过程中骨骼的退行性改变，降低性激素的作用。在本文中，我们研究了雄性斑马鱼（3、6、9 月龄）鳞片中的早期骨老化机制，评估了生理变化以及泼尼松龙（一种促骨质疏松药物）的作用。结果表明，鱼鳞片的矿化率随年龄呈依赖性降低，这一点可通过生长圈测量得到证实。实际上，在基质沉积部位的成骨细胞碱性磷酸酶（ALP）活性被发现逐渐下调。在 63%的 9 月龄鱼鳞片中发现更高的破骨细胞 TRAP 活性，同时在鳞片边缘出现吸收陷窝。基因表达分析表明，老化鳞片中 tnfrsf1b（人 rank 的同源物）的增加可能是吸收刺激的原因。有趣的是，泼尼松龙抑制了鳞片的生理性生长，并在老年鳞片中引起比未处理鱼（3.8%对 1.02%）更显著的骨吸收。骨标志物分析表明，由于泼尼松龙依赖性地刺激 tnfsf11（人 rankl 的同源物），导致 ALP/TRAP 比值显著降低。这些结果首次在低等脊椎动物中证实了存在雄性老年性骨质疏松症。这种新模型有助于确定骨老化的早期机制，并为预防人类与年龄相关的骨改变提供新的治疗策略。
