Analyses on the factors regulating development of ossification of the spinal ligaments

本研究从生物化学、细胞生物学、分子生物学和分子遗传学的角度分析了Npps和瘦素-瘦素受体在脊髓韧带骨化过程中的作用。我们证明，在某些OPLL女性人群中，血清瘦素浓度明显高于非OPLL女性。此外，我们发现编码瘦素受体长形式和短形式的基因在培养的OPLL和非OPLL患者的脊髓韧带细胞中都有表达。瘦素和igf - 1联合使用可增加脊髓韧带细胞的增殖。结果提示，瘦素直接影响脊髓韧带细胞的功能，高瘦素血症似乎参与了OPLL的发生。我们比较了颈椎骨化受限的OPLL患者（C组）和不仅颈椎骨化而且胸腰椎骨化的OPLL患者（TL组）。颈部OPLL常见于男性，而胸腰椎OPLL以女性为主。在女性患者中，TL组的体重指数和血清瘦素浓度显著高于c组。在男性患者中，TL组的糖尿病发生率高于c组。结果表明，胸腰椎OPLL的发生与男性患者的糖代谢偏离、女性患者的肥胖和高瘦素血症密切相关。利用OPLL患者的基因组DNA，我们分析了瘦素受体基因的多态性。而在C组和TL组之间，多态性无显著差异。我们分析了2只小鼠作为OPLL的动物模型。在小鼠中，在编码Npps的基因中发现了一个错义突变。骨桥蛋白在小鼠脊柱肥大过程中过表达。我们认为骨桥蛋白参与了人类OPLL的发生和发展。

In this study, we analyzed the involvement of Npps and leptin-leptin receptors in development of ossification of the spinal ligaments from the standpoint of biochemistry, cell biology, molecular biology and molecular genetics.We demonstrated that, in a certain population of OPLL women, serum concentrations of leptin were significantly higher than those in non-OPLL women. In addition, we showed that genes encoding leptin receptor long form and short form were expressed in cultured spinal ligament cells from both OPLL and non-OPLL patients. Administration of leptin and IGF-I in combination increased the proliferation of spinal ligament cells. The results suggest that leptin directly affects the function of spinal ligament cells, and hyperleptinemia seems to be involved in the development of OPLL.We compared OPLL patients in whom ossification was restricted in cervical spine (Group C) and OPLL patients having ossification not only in cervical spine but also in thoracic and lumbar spines (Group TL). Cervical OPLL frequently occurred in male, whereas thoraco-lumbar OPLL was predominant in female. In female patients, body mass index and serum leptin concentration of Group TL were significantly higher those of Group C.In male patients, incidence of diabetes mellitus was higher in Group TL than in Group C.The results demonstrate that the development of thoraco-lumbar OPLL is strongly related to deviated glucose metabolism in male patients, and obesity and hyperleptinemia in female patients, respectively. Using genomic DNA from OPLL patients, we then analyzed the polymorphism of leptin receptor genes. Between Groups C and TL, however, no significant difference was seen in the polymorphism.We analyzed twy mice as an animal model for OPLL.In the mice, a missense mutation was identified in the gene coding Npps. Osteopontin was over-expressed in the process of spinal hyperostosis in twy mice. We suggest that osteopontin participates in the onset and progression of human OPLL.