Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, SA, Australia; Centre for Orthopaedic and Trauma Research, Faculty of Health Sciences, The University of Adelaide, SA, Australia.
Centre for Orthopaedic and Trauma Research, Faculty of Health Sciences, The University of Adelaide, SA, Australia.
J Steroid Biochem Mol Biol. 2021 Jun;210:105857. doi: 10.1016/j.jsbmb.2021.105857. Epub 2021 Feb 26.
Mature osteoclasts express the vitamin D receptor (VDR) and are able to respond to active vitamin D (1α, 25-dihydroxyvitamin D; 1,25(OH)D) by regulating cell maturation and activity. However, the in vivo consequences of vitamin D signalling directly within functionally mature osteoclasts is only partially understood. To investigate the in vivo role of VDR in mature osteoclasts, conditional deletion of the VDR under control of the cathepsin K promoter (Ctsk/Vdr), was assessed in 6 and 12-week-old mice, either under normal dietary conditions (NormCaP) or when fed a low calcium (0.03 %), low phosphorous (0.08 %) diet (LowCaP). Splenocytes from Ctsk/Vdr mice were co-cultured with MLO-Y4 osteocyte-like cells to assess the effect on osteoclastogenesis. Six-week-old Ctsk/Vdr mice demonstrated a 10 % decrease in vertebral bone volume (p < 0.05), which was associated with increased osteoclast size (p < 0.05) when compared to Vdr control mice. Control mice fed a LowCaP diet exhibited extensive trabecular bone loss associated with increased osteoclast surface, number and size (p < 0.0001). Interestingly, Ctsk/Vdr mice fed a LowCaP diet showed exacerbated loss of bone volume fraction (BV/TV%) and trabecular number (Tb.N), by a further 22 % and 21 %, respectively (p < 0.05), suggesting increased osteoclastic bone resorption activity with the loss of VDR in mature osteoclasts under these conditions. Co-culture of Ctsk/Vdr splenocytes with MLO-Y4 cells increased resulting osteoclast numbers 2.5-fold, which were greater in nuclei density and exhibited increased resorption of dentine compared to osteoclasts derived from Vdr splenocyte cultures. These data suggest that in addition to RANKL-mediated osteoclastogenesis, intact VDR signalling is required for the direct regulation of the differentiation and activity of osteoclasts in both in vivo and ex vivo settings.
成熟的破骨细胞表达维生素 D 受体 (VDR)，并能够通过调节细胞成熟和活性对活性维生素 D (1α, 25-二羟维生素 D; 1,25(OH)D) 作出反应。然而，维生素 D 信号直接在功能成熟的破骨细胞中的体内后果仅部分被理解。为了研究 VDR 在成熟破骨细胞中的体内作用，在正常饮食条件下 (NormCaP) 或在低钙 (0.03%)、低磷 (0.08%) 饮食下 (LowCaP)，使用组织蛋白酶 K 启动子 (Ctsk/Vdr) 控制下对 VDR 进行条件性缺失，在 6 周和 12 周龄的小鼠中进行了评估。将 Ctsk/Vdr 小鼠的脾细胞与 MLO-Y4 成骨细胞样细胞共培养，以评估对破骨细胞生成的影响。与 Vdr 对照小鼠相比，6 周龄的 Ctsk/Vdr 小鼠的椎体骨体积减少了 10% (p < 0.05)，这与破骨细胞大小增加有关 (p < 0.05)。对照小鼠在低钙饮食下表现出广泛的小梁骨丢失，与破骨细胞表面、数量和大小增加有关 (p < 0.0001)。有趣的是，在低钙饮食下，Ctsk/Vdr 小鼠的骨体积分数 (BV/TV%) 和小梁数 (Tb.N) 进一步分别减少了 22%和 21% (p < 0.05)，表明在这些条件下，成熟破骨细胞中 VDR 的丢失导致破骨细胞骨吸收活性增加。Ctsk/Vdr 脾细胞与 MLO-Y4 细胞共培养使破骨细胞数量增加了 2.5 倍，与源自 Vdr 脾细胞培养物的破骨细胞相比，其核密度更大，牙本质吸收增加。这些数据表明，除了 RANKL 介导的破骨细胞生成外，完整的 VDR 信号对于体内和体外环境中破骨细胞的分化和活性的直接调节也是必需的。
