Rixon R H, Whitfield J F, Gagnon L, Isaacs R J, Maclean S, Chakravarthy B, Durkin J P, Neugebauer W, Ross V, Sung W
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario.
J Bone Miner Res. 1994 Aug;9(8):1179-89. doi: 10.1002/jbmr.5650090807.
PTH is regarded conventionally as a catabolic hormone that stimulates osteoclastic resorption of bone. However, it has been known since 1932 that intermittent pulses of PTH stimulate bone formation in animals and humans. PTH independently activates two signal mechanisms: one that stimulates adenylyl cyclase and one that stimulates protein kinase C (PKC). The goal of this study was to use the 3- to 5-month-old ovariectomized (OVX) rat model to determine which of the two signal mechanisms is responsible for the anabolic action of PTH on bone. OVX triggered a large loss of trabecular bone without significantly affecting the normal slow growth of cortical bone in the distal halves of the femora. Daily injections of human hPTH(1-34) fragment (1 nmol/100 g body weight), which stimulated both adenylyl cyclase and membrane-associated PKC activity in osteoblast-like ROS 17/2 rat osteosarcoma cells, stimulated the growth of both cortical and trabecular bone in the OVX rats. Daily injections of the same dose of hPTH(1-31), which stimulated adenylyl cyclase but not PKC in ROS 17/2 cells, stimulated trabecular bone growth in the OVX rats less effectively than hPTH(1-34), but it stimulated cortical bone growth as rapidly and as dramatically as hPTH(1-34). Injections of equimolar amounts of desamino-hPTH(1-34) [N-propionyl(2-3)hPTH-amide], which stimulated PKC as strongly as hPTH(1-34) in ROS 17/2 cells but had a drastically reduced ability to stimulate adenylyl cyclase, or injections of recombinant hPTH(8-84) which stimulated PKC only in the ROS 17/2 cells, did not stimulate cortical or trabecular bone growth in the OVX animals. Thus, cyclic AMP and cyclic AMP-dependent protein kinases may be the primary mediators of the anabolic action of intermittent pulses of PTH on bone in OVX rats.
甲状旁腺激素（PTH）传统上被视为一种分解代谢激素，可刺激破骨细胞对骨的吸收。然而，自1932年以来人们就知道，间歇性脉冲式的PTH可刺激动物和人类的骨形成。PTH可独立激活两种信号机制：一种刺激腺苷酸环化酶，另一种刺激蛋白激酶C（PKC）。本研究的目的是利用3至5月龄去卵巢（OVX）大鼠模型，确定这两种信号机制中哪一种负责PTH对骨的合成代谢作用。OVX导致大量小梁骨丢失，但对股骨远端皮质骨的正常缓慢生长没有显著影响。每日注射人hPTH(1 - 34)片段（1 nmol/100 g体重），该片段可刺激成骨样ROS 17/2大鼠骨肉瘤细胞中的腺苷酸环化酶和膜相关PKC活性，可刺激OVX大鼠的皮质骨和小梁骨生长。每日注射相同剂量的hPTH(1 - 31)，其可刺激ROS 17/2细胞中的腺苷酸环化酶，但不刺激PKC，刺激OVX大鼠小梁骨生长的效果不如hPTH(1 - 34)，但刺激皮质骨生长的速度和程度与hPTH(1 - 34)相同。注射等摩尔量的去氨基-hPTH(1 - 34) [N-丙酰基(2 - 3)hPTH-酰胺]，其在ROS 17/2细胞中刺激PKC的强度与hPTH(1 - 34)相同，但刺激腺苷酸环化酶的能力大幅降低，或注射仅在ROS 17/2细胞中刺激PKC的重组hPTH(8 - 84)，均未刺激OVX动物的皮质骨或小梁骨生长。因此，环磷酸腺苷（cAMP）和cAMP依赖性蛋白激酶可能是间歇性脉冲式PTH对OVX大鼠骨合成代谢作用的主要介质。
