Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
J Bone Miner Res. 2011 Sep;26(9):2026-35. doi: 10.1002/jbmr.433.
Parathyroid hormone (PTH) is widely recognized as a key regulator of mineral ion homeostasis. Daily intermittent administration of PTH is the only currently available anabolic therapy for bone disorders such as osteoporosis. Recent studies have shown that PTH increases transcription and secretion of fibroblast growth factor 23 (FGF-23), another important regulator of phosphate homeostasis and skeletal metabolism. However, the full relationship between PTH and FGF-23 is largely unknown. This study evaluated the effect of FGF-23/Klotho signaling on the phosphaturic and anabolic functions of PTH. Eight-day-old wild-type (WT) Fgf23(-/-) and Kl(-/-) mice were injected with 100 µg/kg PTH(1-34) or vehicle daily for a 2-week-period and then euthanized. Intermittent injection of PTH successfully reduced the serum phosphate levels and reversed the hyperphosphatemia of Fgf23(-/-) and Kl(-/-) mice. Bone changes were analyzed in the distal femur metaphysis by peripheral quantitative computed tomography (pQCT), micro-computed tomography (µCT), and histomorphometry. PTH treatment induced substantial increases in bone mineral density (BMD) and trabecular bone volume in each mouse genotype. Expression of osteoblastic marker genes, including Runx2, Col1, Alp, Ocn, and Sost, was similarly altered. In addition, primary osteoblasts were isolated and treated with 100 nM PTH in vitro. PTH treatment similarly induced cAMP accumulation and phosphorylation of ERK1/2 and CREB in the osteoblasts from each genotype. Taken together, our results demonstrate that FGF-23/Klotho signaling is not essential for the phosphaturic and anabolic functions of PTH, suggesting that PTH can function as a therapeutic agent to improve the skeletal quality of patients even in the presence of abnormal serum FGF-23 levels.
甲状旁腺激素（PTH）被广泛认为是矿物质离子稳态的关键调节剂。每日间歇性给予 PTH 是治疗骨质疏松症等骨骼疾病的唯一可用的合成代谢治疗方法。最近的研究表明，PTH 增加成纤维细胞生长因子 23（FGF-23）的转录和分泌，FGF-23 是另一种重要的磷酸盐稳态和骨骼代谢调节剂。然而，PTH 与 FGF-23 之间的全部关系在很大程度上尚不清楚。本研究评估了 FGF-23/Klotho 信号对 PTH 的磷酸化和合成代谢功能的影响。将 8 天大的野生型（WT）Fgf23(-/-)和 Kl(-/-)小鼠每天注射 100µg/kg PTH(1-34)或载体，持续 2 周，然后处死。间歇性注射 PTH 成功降低了血清磷酸盐水平并逆转了 Fgf23(-/-)和 Kl(-/-)小鼠的高磷酸盐血症。通过外周定量计算机断层扫描（pQCT）、微计算机断层扫描（µCT）和组织形态计量学分析远端股骨干骺端的骨变化。PTH 治疗在每种小鼠基因型中均引起骨矿物质密度（BMD）和小梁骨体积的显著增加。成骨细胞标记基因的表达，包括 Runx2、Col1、Alp、Ocn 和 Sost，也发生了类似的改变。此外，分离并在体外用 100 nM PTH 处理原代成骨细胞。PTH 治疗同样诱导了每个基因型成骨细胞中环磷酸腺苷（cAMP）的积累和 ERK1/2 和 CREB 的磷酸化。总之，我们的结果表明，FGF-23/Klotho 信号对于 PTH 的磷酸化和合成代谢功能不是必需的，这表明 PTH 可以作为一种治疗剂发挥作用，即使在存在异常血清 FGF-23 水平的情况下，也可以改善患者的骨骼质量。
