Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Thier 1101, 50 Blossom Street, Boston, Massachusetts 02114, USA.
J Endocrinol. 2011 Apr;209(1):21-32. doi: 10.1530/JOE-10-0308. Epub 2011 Jan 10.
Parathyroid hormone (PTH) is a major physiologic regulator of calcium, phosphorous, and skeletal homeostasis. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. To understand the role of PTH signaling through the PTH/PTHrP receptors (PPR) in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone, we have generated mice in which PPR expression is specifically ablated in osteocytes. Transgenic mice in which the 10 kb-Dmp1 promoter drives a tamoxifen-inducible Cre-recombinase were mated with animals in which exon 1 of PPR is flanked by lox-P sites. In these animals, osteocyte-selective PPR knockout (Ocy-PPR(cKO) mice) could be induced by administration of tamoxifen. Histological analysis revealed a reduction in trabecular bone and mild osteopenia in Ocy-PPR(cKO) mice. Reduction of trabeculae number and thickness was also detected by micro-computed tomography analysis whereas bone volume fraction (BV/TV%) was unchanged. These findings were associated with an increase in Sost and sclerostin expression. When Ocy-PPR(cKO) mice were subjected to a low-calcium diet to induce secondary hyperparathyroidism, their blood calcium levels were significantly lower than littermate controls. Moreover, PTH was unable to suppress Sost and sclerostin expression in the Ocy-PPR(cKO) animals, suggesting an important role of PTH signaling in osteocytes for proper bone remodeling and calcium homeostasis.
甲状旁腺激素 (PTH) 是钙、磷和骨骼内稳态的主要生理调节剂。成骨细胞系的细胞是 PTH 在骨骼中作用的主要靶标，最近的证据表明，骨细胞可能在 PTH 的合成代谢作用中很重要。为了了解 PTH 通过 PTH/PTHrP 受体 (PPR) 在骨细胞中的信号转导作用，并确定这些细胞在介导激素作用中的作用，我们已经生成了 PPR 表达在骨细胞中特异性缺失的小鼠。将 10 kb-Dmp1 启动子驱动的 tamoxifen 诱导型 Cre 重组酶的转基因小鼠与 PPR 外显子 1 侧翼带有 lox-P 位点的动物交配。在这些动物中，通过给予他莫昔芬可诱导骨细胞特异性 PPR 敲除 (Ocy-PPR(cKO) 小鼠)。组织学分析显示，Ocy-PPR(cKO) 小鼠的小梁骨减少和轻度骨质疏松症。通过 micro-CT 分析还检测到小梁数量和厚度减少，而骨体积分数 (BV/TV%) 保持不变。这些发现与 Sost 和 Sclerostin 表达增加有关。当 Ocy-PPR(cKO) 小鼠接受低钙饮食以诱导继发性甲状旁腺功能亢进时，其血钙水平明显低于同窝对照。此外，PTH 无法抑制 Ocy-PPR(cKO) 动物中的 Sost 和 Sclerostin 表达，表明 PTH 信号在骨细胞中对适当的骨重塑和钙稳态具有重要作用。
