Jilka Robert L, O'Brien Charles A, Ali A Afshan, Roberson Paula K, Weinstein Robert S, Manolagas Stavros C
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, Slot 587, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR, USA.
Bone. 2009 Feb;44(2):275-86. doi: 10.1016/j.bone.2008.10.037. Epub 2008 Oct 22.
Intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of cancellous and periosteal bone by increasing the number of osteoblasts. Previous studies of ours in mice demonstrated that intermittent PTH increases cancellous osteoblast number at least in part by attenuating osteoblast apoptosis, but the mechanism responsible for the anabolic effect of the hormone on periosteal bone is unknown. We report that daily injections of 100 ng/g of PTH(1-34) to 4-6 month old mice increased the number of osteoblasts on the periosteum of lumbar vertebrae by 2-3 fold as early as after 2 days. However, the prevalence of apoptotic periosteal osteoblasts was only 0.2% in vehicle treated animals, which is approximately 20-fold lower than is the case for cancellous osteoblasts. Moreover, PTH did not have a discernable effect on periosteal osteoblast apoptosis. Administration of BrdU for 4 days failed to label periosteal osteoblasts under either basal conditions or following administration of PTH. Cancellous osteoblasts, on the other hand, were labeled under basal conditions, but PTH did not increase the percentage of BrdU-positive cells. Thus, intermittent PTH does not increase cancellous or periosteal osteoblast number by stimulating the proliferation of osteoblast progenitors. Consistent with high turnover of cancellous osteoblasts as compared to that of periosteal osteoblasts, ganciclovir-induced ablation of replicating osteoblast progenitors in mice expressing thymidine kinase under the control of the 3.6 kb rat Col1A1 promoter resulted in disappearance of osteoblasts from cancellous bone over a 7-14 day period, whereas periosteal osteoblasts were unaffected. However, 14 days of pre-treatment with ganciclovir prevented PTH anabolism on periosteal bone. We conclude that in cancellous bone, attenuation of osteoblast apoptosis by PTH increases osteoblast number because their rate of apoptosis is high, making this effect of the hormone profound. However, in periosteal bone where the rate of osteoblast apoptosis is low, PTH must exert pro-differentiating and/or pro-survival effects on post-mitotic pre-osteoblasts. Targeting the latter cells is an effective mechanism for increasing osteoblast number in periosteal bone where the production of osteoblasts from replicating progenitors is slow.
间歇性给予甲状旁腺激素（PTH）可通过增加成骨细胞数量来刺激松质骨和骨膜骨表面的骨形成。我们之前在小鼠身上的研究表明，间歇性PTH至少部分通过减弱成骨细胞凋亡来增加松质骨成骨细胞数量，但该激素对骨膜骨的合成代谢作用机制尚不清楚。我们报告称，每天给4至6月龄小鼠注射100 ng/g的PTH（1-34），早在2天后就使腰椎骨膜上的成骨细胞数量增加了2至3倍。然而，在接受载体处理的动物中，骨膜成骨细胞的凋亡率仅为0.2%，这比松质骨成骨细胞的凋亡率低约20倍。此外，PTH对骨膜成骨细胞凋亡没有明显影响。在基础条件下或给予PTH后，连续4天给予BrdU未能标记骨膜成骨细胞。另一方面，松质骨成骨细胞在基础条件下被标记，但PTH并未增加BrdU阳性细胞的百分比。因此，间歇性PTH不会通过刺激成骨细胞祖细胞的增殖来增加松质骨或骨膜骨的成骨细胞数量。与松质骨成骨细胞相比，骨膜成骨细胞的更新率较高，在3.6 kb大鼠Col1A1启动子控制下表达胸苷激酶的小鼠中，更昔洛韦诱导复制性成骨细胞祖细胞的消融导致松质骨中的成骨细胞在7至14天内消失，而骨膜成骨细胞未受影响。然而，更昔洛韦预处理14天可阻止PTH对骨膜骨的合成代谢作用。我们得出结论，在松质骨中，PTH减弱成骨细胞凋亡可增加成骨细胞数量，因为它们的凋亡率很高，使得该激素的这一作用显著。然而，在骨膜骨中，成骨细胞凋亡率较低，PTH必须对有丝分裂后的前成骨细胞发挥促分化和/或促存活作用。针对后一种细胞是增加骨膜骨中骨细胞数量的有效机制，因为从复制祖细胞产生成骨细胞的速度较慢。
