Kneissel Michaela, Studer Anne, Cortesi Reto, Susa Mira
Bone Metabolism, Novartis Institutes for BioMedical Research Basel, WK-125.10.15, CH-4002 Basel, Switzerland.
Bone. 2005 Feb;36(2):202-14. doi: 10.1016/j.bone.2004.11.006.
Excess of Vitamin A (retinol) and related compounds (retinoids) induces bone fragility and is associated with increased hip fracture incidence in humans. Yet, their impact on the adult skeleton has been studied in relatively little detail. It is assumed that they induce generalized bone loss and decrease long-bone thickness due to reduction of radial bone growth. Here we characterized early skeletal responses of adult rodents to retinoid treatment, revealing novel aspects of retinoid action on the mature skeleton. The retinoid Ro 13-6298, given subcutaneously for 4 days, induced bone loss in the hind limbs of 12- and 56-week-old rats and of 15-week-old mice. In vivo monitoring of bone mass and geometry changes by peripheral quantitative computed tomography demonstrated that bone mass decline was due to subperiosteal cortical bone loss, which induced a shrinkage of bone diameter, whilst cancellous bone mass was preserved. We observed that the native retinoic acid isomer all-trans RA induced an identical pattern of bone loss. Histomorphometric evaluation revealed that increased subperiosteal osteoclastic bone resorption caused the cortical bone destruction. Interestingly, bone resorption was suppressed in cancellous bone, which was in agreement with reduced in vitro formation of osteoclasts from bone marrow cells that were derived from the proximity of cancellous bone. The retinoid-induced increase in subperiosteal bone resorption could be blocked by bisphosphonate as direct potent inhibitor of osteoclast action, but not by estradiol. Retinoid treatment induced a reduction of bone-forming surfaces at the subperiosteal site, but not in cancellous bone. In vitro osteoblast performance was also reduced or unchanged, depending on the cellular system used and assay type/duration. In conclusion, our studies revealed that the impact of retinoids on bone is highly bone-compartment-specific at early treatment phases. Furthermore, we showed that bone diameter shrinks in the adult skeleton after retinoid treatment due to subperiosteal osteoclastic bone resorption. Thus, retinoid-induced bone thinning is not only due to reduced radial bone growth as previously assumed. Our findings might explain why high intake of retinol is associated with increased hip fracture risk in the elderly and suggest a therapy to prevent such potential negative effects.
维生素A（视黄醇）及相关化合物（类视黄醇）过量会导致骨骼脆弱，且与人类髋部骨折发生率增加有关。然而，它们对成年骨骼的影响尚未得到较为详细的研究。据推测，它们会导致全身性骨质流失，并因桡骨生长减少而使长骨厚度降低。在此，我们对成年啮齿动物对类视黄醇治疗的早期骨骼反应进行了表征，揭示了类视黄醇对成熟骨骼作用的新方面。皮下注射类视黄醇Ro 13 - 6298 4天，可导致12周龄和56周龄大鼠以及15周龄小鼠后肢骨质流失。通过外周定量计算机断层扫描对骨量和几何形状变化进行体内监测表明，骨量下降是由于骨膜下皮质骨流失所致，这导致骨直径缩小，而松质骨量得以保留。我们观察到天然视黄酸异构体全反式视黄酸诱导出相同的骨质流失模式。组织形态计量学评估显示，骨膜下破骨细胞骨吸收增加导致皮质骨破坏。有趣的是，松质骨中的骨吸收受到抑制，这与来自松质骨附近的骨髓细胞体外破骨细胞形成减少相一致。类视黄醇诱导的骨膜下骨吸收增加可被作为破骨细胞作用直接强效抑制剂的双膦酸盐阻断，但不能被雌二醇阻断。类视黄醇治疗导致骨膜下部位的骨形成表面减少，但松质骨中未减少。体外成骨细胞性能也有所降低或未改变，这取决于所使用的细胞系统以及检测类型/持续时间。总之，我们的研究表明，在治疗早期，类视黄醇对骨骼的影响具有高度的骨区特异性。此外，我们表明类视黄醇治疗后成年骨骼中的骨直径会因骨膜下破骨细胞骨吸收而缩小。因此，类视黄醇诱导的骨质变薄不仅如先前所认为的那样是由于桡骨生长减少。我们的研究结果或许可以解释为何高剂量视黄醇摄入与老年人髋部骨折风险增加有关，并提示一种预防此类潜在负面影响的治疗方法。
