Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine

Abstract

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common form of human myelopathy caused by a compression of the spinal cord by ectopic ossification of spinal ligaments1,2. To elucidate the genetic basis for OPLL, we have been studying the ttw (tiptoe walking; previously designated twy) mouse, a naturally occurring mutant which exhibits ossification of the spinal ligaments very similar to human OPLL (Refs 3,4). Using a positional candidate-gene approach, we determined the ttw phenotype is caused by a nonsense mutation (glycine 568 to stop) in the Npps gene which encodes nucleotide pyrophosphatase. This enzyme regulates soft-tissue calcification and bone mineralization by producing inorganic pyrophosphate, a major inhibitor of calcification5,6,7,8. The accelerated bone formation characteristic of ttw mice is likely to result from dysfunction of NPPS caused by predicted truncation of the gene product, resulting in the loss of more than one-third of the native protein. Our results may lead to novel insights into the mechanism of ectopic ossification and the aetiology of human OPLL.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Phenotypic similarity between OPLL and the ttw mouse.
Figure 2: Linkage map and physical contig of YAC, BAC and cosmid clones at the ttw locus on mouse chromosome 10.
Figure 3: The ttw mutation. a, Sequence analysis of the Npps cDNA.
Figure 4: Schematic structure of mouse nucleotide pyrophosphatase (Npps).

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Ono, K., Ota, H., Tada, K., Hamada, H. & Takaoka, K. Ossified posterior longitudinal ligament. A clinicopathologic study. Spine 2, 126–132 (1977).

  2. 2

    Tsuyama, N. Ossification of the posterior longitudinal ligament of the spine. Clin. Orthop. 184, 71–84 ( 1984).

  3. 3

    Yamazaki, M. et al. Increased type XI collagen expression in the spinal hyperostotic mouse (TWY/TWY) . Calcif. Tissue Int. 48, 182– 189 (1991).

  4. 4

    Goto, S. & Yamazaki, M. Pathogenesis of ossification of the spinal ligaments. in Ossification of the Posterior Longitudinal Ligament (eds Yonenobu, K., Sakou, T. & Ono, K.) 29– 37 (Springer-Verlag, Tokyo, 1997).

  5. 5

    Caswell, A.M., Ali, S.Y. & Russell, R.G. Nucleoside triphosphate pyrophosphatase of rabbit matrix vesicles, a mechanism for the generation of inorganic pyrophosphate in epiphyseal cartilage. Biochim. Biophys. Acta 924, 276 –283 (1987).

  6. 6

    Caswell, A.M. & Russell, R.G. Evidence that ecto-nucleoside-triphosphate pyrophosphatase serves in the generation of extracellular inorganic pyrophosphate in human bone and articular cartilage. Biochim. Biophys. Acta 966, 310–317 (1988).

  7. 7

    Huang, R. et al. Expression of the murine plasma cell nucleotide pyrophosphohydrolase PC-1 is shared by human liver, bone, and cartilage cells: regulation of PC-1 expression in osteosarcoma cells by transforming growth factor-beta. J. Clin. Invest. 94, 560–567 ( 1994).

  8. 8

    Fleisch, H. Diphosphonates: History and mechanisms of action. Metab. Bone Dis. Relat. Res. 3, 279–288 ( 1981).

  9. 9

    Albinni, U., Merlini, L., Terayama, K., Ohtsuka, K. & Savini, R. Epidemiologia radiographica delle ossificazioni dei legamenti e delle degenerazione discale del rachide cervicale. Chir. Organi. Mov. 70, 15–22 (1982).

  10. 10

    Firooznia, H. et al. Calcification and ossification of posterior longitudinal ligament of spine. Its role in secondary narrowing of spinal canal and cord compression. NY State J. Med. 82, 1193–1198 (1982).

  11. 11

    Tsuyama, N. Ossification of the posterior longitudinal ligament of the spine. Clin. Orthop. 184, 71–84 ( 1984).

  12. 12

    Ohtsuka, K., Terayama, K. & Yanagihara, M. A radiological population study on the ossification of the posterior longitudinal ligament in the spine. Arch. Orthop. Trauma Surg. 106, 89–93 (1987).

  13. 13

    Terayama, K. Genetic studies on ossification of the posterior longitudinal ligament of the spine. Spine 14, 1184–1191 ( 1989).

  14. 14

    Sakou, T., Taketomi, Y., Suematsu, N. & Atsuta, Y. Genetic study of ossification of the posterior longitudinal ligament in the cervical spine with human leukocyte antigen haplotype. Spine 6, 1249–1252 (1991).

  15. 15

    Hosoda, Y., Yoshimura, Y. & Higaki, S. A new breed of mouse showing multiple osteochondral lesions - twy mouse. Ryumachi 21 (suppl), 157–164 (1981).

  16. 16

    Okawa, A. et al. Mapping of a gene responsible for twy (tip-toe walking Yoshimura), a mouse model of ossification of the posterior longitudinal ligament of the spine (OPLL). Mamm. Genome 9, 155– 156 (1998).

  17. 17

    Terkeltaub, R., Rosenbach, M., Fong, F. & Goding, J. A causal link between nucleotide pyrophosphohydrolase overactivity and increased intracellular Ppi generation is demonstrated by transfection of cultured fibroblasts and osteoblast with PC-1 (plasma cell membrane glycoprotein-1): relevance to CPPD deposition disease. Arthritis Rheum. 37, 934– 941 (1994).

  18. 18

    Rebbe, N.F., Tong, B.D., Finley, E.M. & Hickman, S. Identification of nucleotide pyrophosphatase/alkaline phosphodiesterase I activity associated with the mouse plasma cell differentiation antigen PC-1. Proc. Natl Acad. Sci. USA 88, 5192–5196 (1991).

  19. 19

    Harahap, A.R. & Goding, J.W. Distribution of the murine plasma cell antigen PC-1 in non-lymphoid tissues. J. Immun. 141, 2317–2320 (1988).

  20. 20

    Siegel, S.A., Hummel, C.F. & Carty, R.P. The role of nucleoside triphosphate pyrophosphohydrolase in in vitro nucleoside triphosphate- dependent matrix vesicle calcification. J. Biol. Chem. 258, 8601–8607 ( 1983).

  21. 21

    Hsu, H.H. Purification and partial characterization of ATP pyrophosphohydrolase from fetal bovine epiphyseal cartilage. J. Biol. Chem. 258, 3463– 3468 (1983).

  22. 22

    Oyajobi, B.O., Russell, R.G. & Caswell, A.M. Modulation of ecto-nucleoside triphosphate pyrophosphatase activity of human osteoblast-like bonecells by 1 alpha, 25-dihydroxyvitamin D3, 24R,25-dihydroxyvitamin D3, parathyroid hormone, and dexamethasone. J. Bone Miner. Res. 9, 1259–1266 (1994).

  23. 23

    van Driel, I.R. & Goding, J.W. Plasma cell membrane glycoprotein PC-1. J. Biol. Chem. 262, 4882– 4887 (1987).

  24. 24

    Belli, S.I., van Driel, I.R. & Goding, J.W. Identification and Characterization of a soluble form of the plasma cell membrane glycoprotein PC-1 (5´-nucleotide phosphodiesterase) . Eur. J. Biochem. 217, 421– 428 (1993).

  25. 25

    Terakado, A. et al. Elevation of alkaline phosphatase activity induced by parathyroid hormone in osteoblast-like cells from the spinal hyperostotic mouse TWY (twy/twy) . Calcif. Tissue Int. 56, 135– 139 (1995).

  26. 26

    Dietrich, W. et al. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131, 423–447 ( 1992).

  27. 27

    Vidal, S.M., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469–485 (1993).

Download references

Acknowledgements

We thank K. Hioki, Y. Endo and T. Shiroishi for preparing the animal crosses, and T. Tanaka for helpful discussion. This work was supported in part by grants from the Ministry of Health and Welfare and from the Ministry of Education, Culture, Sports and Science of Japan.

Author information

Correspondence to Yusuke Nakamura.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Okawa, A., Nakamura, I., Goto, S. et al. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet 19, 271–273 (1998). https://doi.org/10.1038/956

Download citation

Further reading