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

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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.