Bone Marrow Cell Development and Signal Transduction in Bone Loss due to Skeletal Unloading.

2002年，我们的数据显示，p53（-/-）小鼠尾巴悬吊后的骨小梁骨量和骨形成得以保留，这与p53（-/-）小鼠胫骨骨髓培养物中alp阳性CFU-f和矿化结节形成密切相关。机械卸载导致的骨质流失可能与细胞内p53-p21信号传导的促进有关。我们还证明，通过诱导型一氧化氮合酶产生一氧化氮对于机械重新加载时骨形成的刺激是必不可少的。2003年，我们阐明了骨骼卸载减轻小鼠胫骨中间歇性甲状旁腺激素（PTH）（1-34）的合成代谢作用，这与抑制PTH诱导的骨髓细胞中c-fos mRNA的增加有关。pth诱导的c-fos mRNA的升高被抑制，但Osterix和RANKL mRNA的升高保持不变。卸载促进了pth相关的破骨细胞形成，似乎与减少骨髓细胞中pth依赖性的c-fos mRNA的增加有关，从而延缓了成骨分化的进展。2004年，我们的数据表明，骨卸除后成骨潜能的下降与骨髓细胞PECAM-1 （CD31）表达的减少有关，在甲状旁腺切除小鼠中，骨卸除后破骨细胞表面和数量的显著增加受到抑制，与胫骨骨髓细胞中RANKL mRNA高表达的减少密切相关。通过这3年，我们阐明了骨骼卸载通过促进骨髓细胞内p53-p21信号传导和减少PECAM-1表达来减少骨形成，骨骼卸载导致的破骨细胞生成增强与骨髓细胞中甲状旁腺激素信号传导促进RANKL表达升高有关。

In 2002, our data showed that trabecular bone mass and bone formation were preserved after tail-suspension in p53(-/-) mice, closely associated with ALP-positive CFU-f and mineralized nodule formation in marrow cultures obtained from tibias of p53(-/-) mice. Bone loss due to mechanical unloading can be related to the facilitation of intracellular p53-p21 signaling. We also demonstrated that generation of nitric oxide through inducible nitric oxide synthase is essential for the stimulation of bone formation upon mechanical reloading.In 2003, we clarified that skeletal unloading alleviated the anabolic action of intermittent parathyroid hormone (PTH) (1-34) in mouse tibia in association with inhibition of PTH-induced increase in c-fos mRNA in bone marrow cells. The PTH-induced increase in c-fos mRNA was depressed, but the increases in Osterix and RANKL mRNA were maintained. Unloading promoted the PTH-associated osteoclastogenesis and seemed to delay the progression of osteogenic differentiation in association with reduction of the PTH-dependent increase of c-fos mRNA in bone marrow cells.In 2004, our data demonstrated that the decreased osteogenic potential after unloading was related to the reduction of PECAM-1 (CD31) expression in bone marrow cells, and that significant increases in osteoclast surface and number after skeletal unloading were suppressed in thyroparathyroidectomized mice, closely associated with the reduction in the high expression of RANKL mRNA in the tibial bone marrow cells.Through these 3 years, we clarified that skeletal unloading reduced bone formation by the facilitation of intracellular p53-p21 signaling and the reduction of PECAM-1 expression in bone marrow cells, and that enhanced osteoclastogenesis due to skeletal unloading is related to the elevation of RANKL expression by the facilitation of parathyroid hormone signaling in bone marrow cells.