Whitfield James F
Institute for Biological Sciences, Montreal Road Campus, National Research Council of Canada, Ottawa, Ontario, Canada, K1A 0R6.
J Cell Biochem. 2005 Oct 1;96(2):278-84. doi: 10.1002/jcb.20526.
Forty-seven years ago, the parathyroid hormone (PTH) in one injection of Lilly's old bovine parathyroid extract, PTE, was found to greatly increase the 30-day survival of heavily X-irradiated rats when given from 18 h before to as long as 3 h after irradiation but no later. This was the first indication that PTH might stimulate hematopoiesis. Recent studies have confirmed the relation between PTH and hematopoiesis by showing that hPTH-(1-34)OH increases the size of the hematopoietic stem cell pool in mice. The peptide operates through a cyclic AMP-mediated burst of Jagged 1 production in osteoblastic cells lining the stem cells' niches on trabecular bone surfaces. The osteoblastic cells' Jagged 1 increases the hematopoietic stem cell pool by activating Notch receptors on attached stem cells. PTH-triggered cyclic AMP signals also directly stimulate the proliferation of the hematopoietic stem cells. However, the single PTH injection in the early experiments using PTE probably increased the survival of irradiated rats mainly by preventing the damaged hematopoietic progenitors from irreversibly initiating self-destructive apoptogenesis during the first 5 h after irradiation. It has also been shown that several daily injections of hPTH-(1-34)OH enable lethally irradiated mice to survive by stimulating the growth of transplanted normal bone marrow cells. If the osteogenic PTHs currently entering or on the verge of entering the market for treating osteoporosis can also drive hematopoiesis in humans as well as rodents, they could be potent tools for reducing the damage inflicted on bone marrow by cytotoxic cancer chemotherapeutic drugs and ionizing radiation.
47年前，人们发现礼来公司旧版牛甲状旁腺提取物（PTE）单次注射中的甲状旁腺激素（PTH），若在照射前18小时至照射后长达3小时（但不能更晚）给药，能显著提高受大剂量X射线照射大鼠的30天存活率。这是PTH可能刺激造血的首个迹象。最近的研究通过表明hPTH-(1-34)OH可增加小鼠造血干细胞池的大小，证实了PTH与造血之间的关系。该肽通过在小梁骨表面干细胞龛内衬的成骨细胞中由环磷酸腺苷介导的Jagged 1产生爆发来发挥作用。成骨细胞的Jagged 1通过激活附着干细胞上的Notch受体来增加造血干细胞池。PTH触发的环磷酸腺苷信号也直接刺激造血干细胞的增殖。然而，在早期使用PTE的实验中，单次注射PTH可能主要是通过防止受损的造血祖细胞在照射后的前5小时内不可逆地启动自我毁灭的凋亡过程，从而提高受照射大鼠的存活率。研究还表明，每天多次注射hPTH-(1-34)OH可通过刺激移植的正常骨髓细胞生长，使受致死剂量照射的小鼠存活下来。如果目前正在进入或即将进入治疗骨质疏松症市场的促骨生成PTHs也能在人类和啮齿动物中驱动造血，那么它们可能成为减少细胞毒性癌症化疗药物和电离辐射对骨髓造成损害的有力工具。
