Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland.
Department of Biotechnology, Agricultural University of Athens, Iera Odos, Athens, Greece.
J Bone Miner Res. 2021 Aug;36(8):1636-1645. doi: 10.1002/jbmr.4307. Epub 2021 Apr 28.
Receptor activator of nuclear factor-κΒ ligand (RANKL) is necessary and sufficient to promote osteoclastogenesis and a key pathogenic factor in osteoporosis. Failure of periosteal apposition to compensate for bone loss due to endosteal resorption further contributes to bone fragility. Whether these two processes are biologically related, however, remains unknown. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we first examined cortical bone parameters at distal radius and tibia in postmenopausal women (PMW) as well as in cadaveric human adult humeri. Increases in medullary area were negatively correlated with cortical bone volume but positively with total bone volume, and this relationship was stronger in the dominant arm, suggesting a mechanically driven process. To investigate the role of RANKL in this dual process, we used mice overexpressing huRANKL (huRANKLTg ). Trabecular and cortical bone volume (Ct.BV) are reduced in these mice, whereas cortical total volume (Ct.TV) is increased. In these bones, Sost mRNA levels are downregulated and periostin (Postn) mRNA levels upregulated, hence providing a positive message for periosteal bone formation. In turn, genetic deletion of Postn in huRANKLTg mice prevented the increase in Ct.TV and aggravated bone fragility. In contrast, cathepsin K (Ctsk) ablation improved Ct.TV in both huRANKLTg and wild-type (WT) mice and stimulated periosteal bone formation, while augmenting Postn protein levels. Therefore, bone strength in huRANKLTg /Ctsk mice was restored to WT levels. These findings suggest that high levels of RANKL not only induce endosteal bone loss but may somewhat restrict periosteal bone formation by triggering periostin degradation through cathepsin K, hence providing a biological mechanism for the observed limited increase in cortical area in postmenopausal women. © 2021 American Society for Bone and Mineral Research (ASBMR).
核因子-κΒ 受体激活剂配体（RANKL）是促进破骨细胞形成的必要和充分条件，也是骨质疏松症的关键致病因素。骨皮质的成骨作用不足以补偿骨小梁的吸收，这进一步导致了骨的脆弱。然而，这两个过程是否在生物学上相关尚不清楚。我们首次使用高分辨率外周定量计算机断层扫描（HR-pQCT）检测了绝经后妇女（PMW）和成人尸体肱骨的桡骨远端和胫骨骨干皮质骨参数。骨髓腔面积的增加与皮质骨体积呈负相关，但与总骨体积呈正相关，而在优势臂中这种相关性更强，这表明这是一个力学驱动的过程。为了研究 RANKL 在这个双过程中的作用，我们使用了过表达 huRANKL（huRANKLTg）的小鼠。这些小鼠的骨小梁和皮质骨体积（Ct.BV）减少，而皮质总容积（Ct.TV）增加。在这些骨骼中，SostmRNA 水平下调，periostin（Postn）mRNA 水平上调，从而为骨膜成骨提供了积极的信号。反过来，在 huRANKLTg 小鼠中遗传缺失 Postn 阻止了 Ct.TV 的增加，并加重了骨脆性。相比之下，组织蛋白酶 K（Ctsk）的缺失在 huRANKLTg 和野生型（WT）小鼠中均改善了 Ct.TV，并刺激了骨膜成骨，同时增加了 Postn 蛋白水平。因此，huRANKLTg/Ctsk 小鼠的骨强度恢复到 WT 水平。这些发现表明，高水平的 RANKL 不仅诱导骨内吸收，而且可能通过组织蛋白酶 K 触发 periostin 降解在一定程度上限制骨膜成骨，从而为绝经后妇女观察到的皮质骨面积有限增加提供了生物学机制。
