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

2002年，我们的研究结果表明，P53(-/-)小鼠悬吊后骨小梁和骨形成得以保留，与ALP阳性的CFU-f和P53(-/-)小鼠胫骨骨髓培养中矿化结节的形成密切相关。机械卸载导致的骨丢失可能与促进细胞内p53-p21信号转导有关。我们还证明了通过诱导型一氧化氮合酶产生一氧化氮是机械再负荷时刺激骨形成所必需的。2003年，我们阐明了骨骼卸载减轻了间歇性甲状旁腺激素(PTH)(1-34)在小鼠胫骨的合成代谢作用，并与抑制PTH诱导的骨髓细胞c-fos mRNA的增加有关。抑制甲状旁腺素诱导的c-fos基因表达增加，但维持Osterix和RANKL基因表达的增加。甲状旁腺切除小鼠去甲状旁腺后破骨细胞表面和数量的显著增加，与胫骨骨髓细胞RANKL mRNA高表达的减少密切相关。2004年，我们的研究表明，去甲状旁腺小鼠去甲状旁腺后成骨潜能降低与骨髓细胞中PECAM-1(CD31)表达降低有关。我们阐明，骨骼卸载通过促进细胞内P53-p21信号转导和减少骨髓细胞中PECAM-1的表达来减少骨形成，而骨骼卸载促进破骨细胞的形成与促进骨髓细胞甲状旁腺激素信号转导RANKL表达有关。

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.