Demiralp Burak, Chen Hen-Li, Koh Amy J, Keller Evan T, McCauley Laurie K
Department of Periodontics/Prevention/Geriatrics, Medical School, University of Michigan Ann Arbor 48109, USA.
Endocrinology. 2002 Oct;143(10):4038-47. doi: 10.1210/en.2002-220221.
PTH has anabolic and catabolic actions in bone that are not clearly understood. The protooncogene c-fos and other activating protein 1 family members are critical transcriptional mediators in bone, and c-fos is up-regulated by PTH. The purpose of this study was to examine the mechanisms of PTH and the role of c-fos in PTH-mediated anabolic actions in bone. Mice with ablation of c-fos (-/-) and their wild-type (+/+) and heterozygous (+/-) littermates were administered PTH for 17 d. The +/+ mice had increased femoral bone mineral density (BMD), whereas -/- mice had reduced BMD after PTH treatment. PTH increased the ash weight of +/+ and +/-, but not -/-, femurs and decreased the calcium content of -/-, but not +/+ or +/-, femurs. Histomorphometric analysis showed that PTH increased trabecular bone volume in c-fos +/+, +/- vertebrae, but, in contrast, decreased trabecular bone in -/- vertebrae. Serum calcium levels in +/+ mice were greater than those in -/- mice, and PTH increased calcium in -/- mice. Histologically, PTH resulted in an exacerbation of the already widened growth plate and zone of hypertrophic chondrocytes but not the proliferating zone in -/- mice. PTH also increased calvarial thickness in +/+ mice, but not -/- mice. The c-fos -/- mice had lower bone sialoprotein and osteocalcin (OCN), but unaltered PTH-1 receptor mRNA expression in calvaria, suggesting an alteration in extracellular matrix. Acute PTH injection (8 h) resulted in a decrease in osteocalcin mRNA expression in wild-type, but unaltered expression in -/-, calvaria. These data indicate that c-fos plays a critical role in the anabolic actions of PTH during endochondral bone growth.
甲状旁腺激素（PTH）在骨骼中具有合成代谢和分解代谢作用，但其机制尚不清楚。原癌基因c-fos和其他活化蛋白1家族成员是骨骼中的关键转录调节因子，且c-fos会被PTH上调。本研究旨在探讨PTH的作用机制以及c-fos在PTH介导的骨骼合成代谢作用中的角色。对c-fos基因敲除（-/-）小鼠及其野生型（+/+）和杂合子（+/-）同窝小鼠给予PTH处理17天。PTH处理后，+/+小鼠股骨骨矿物质密度（BMD）增加，而-/-小鼠的BMD降低。PTH增加了+/+和+/-小鼠股骨的灰重，但未增加-/-小鼠的；PTH降低了-/-小鼠股骨的钙含量，但未降低+/+和+/-小鼠的。组织形态计量学分析显示，PTH增加了c-fos +/+、+/-小鼠椎骨的骨小梁体积，相反，却减少了-/-小鼠椎骨的骨小梁。+/+小鼠的血清钙水平高于-/-小鼠，PTH使-/-小鼠的血钙升高。组织学上，PTH导致-/-小鼠已增宽的生长板和肥大软骨细胞区进一步加剧，但增殖区未受影响。PTH还增加了+/+小鼠颅骨的厚度，但未增加-/-小鼠的。c-fos -/-小鼠颅骨中的骨唾液蛋白和骨钙素（OCN）较低，但PTH-1受体mRNA表达未改变，提示细胞外基质发生改变。急性注射PTH（8小时）导致野生型小鼠颅骨中骨钙素mRNA表达降低，但-/-小鼠颅骨中的表达未改变。这些数据表明，c-fos在软骨内骨生长过程中PTH的合成代谢作用中起关键作用。
