Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: A unified model of the mechanisms of initiation of skeletal calcification

Abstract

Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Alkaline phosphatase (TNAP) plays a crucial role promoting mineralization of the extracellular matrix by restricting the concentration of the calcification inhibitor inorganic pyrophosphate (PPi). Mutations in the TNAP gene cause hypophosphatasia, a heritable form of rickets and osteomalacia. Here we show that PHOSPHO1, a phosphatase with specificity for phosphoethanolamine and phosphocholine, plays a functional role in the initiation of calcification and that ablation of PHOSPHO1 and TNAP function prevents skeletal mineralization. Phospho1−/− mice display growth plate abnormalities, spontaneous fractures, bowed long bones, osteomalacia, and scoliosis in early life. Primary cultures of Phospho1−/− tibial growth plate chondrocytes and chondrocyte-derived matrix vesicles (MVs) show reduced mineralizing ability, and plasma samples from Phospho1−/− mice show reduced levels of TNAP and elevated plasma PPi concentrations. However, transgenic overexpression of TNAP does not correct the bone phenotype in Phospho1−/− mice despite normalization of their plasma PPi levels. In contrast, double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality. We conclude that PHOSPHO1 has a nonredundant functional role during endochondral ossification, and based on these data and a review of the current literature, we propose an inclusive model of skeletal calcification that involves intravesicular PHOSPHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP, nucleotide pyrophosphatase phosphodiesterase-1, and collagen in the extravesicular progression of mineralization. © 2011 American Society for Bone and Mineral Research.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 49

1. 1.

   Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol. 1969;41:59-72.

   Not in our library10.1083/jcb.41.1.59

2. 2.

   Ali SY, Sajdera SW, Anderson HC. Isolation and characterization of calcifying matrix vesicles from epiphyseal cartilage. Proc Natl Acad Sci USA. 1970;67:1513-1520.

   Not in our library10.1073/pnas.67.3.1513

3. 3.

   Register TC, McLean FM, Low MG, Wuthier RE. Roles of alkaline phosphatase and labile internal mineral in matrix vesicle–mediated calcification: effect of selective release of membrane-bound alkaline phosphatase and treatment with isosmotic pH 6 buffer. J Biol Chem. 1986;261:9354-9360.

   Not in our library

4. 4.

   Anderson HC, Garimella R, Tague SE. The role of matrix vesicles in growth plate development and biomineralization. Front Biosci. 2005;10:822-837.

   Not in our library10.2741/1576

5. 5.

   Meyer JL. Can biological calcification occur in the presence of pyrophosphate? Arch. Biochem Biophys. 1984;231:1-8.

   Not in our library10.1016/0003-9861(84)90356-4

6. 6.

   Moss DW, Eaton RH, Smith JK, Whitby LG. Association of inorganic-pyrophosphatase activity with human alkaline-phosphatase preparations. Biochem J. 1967;102:53-57.

   Not in our library10.1042/bj1020053

7. 7.

   Majeska RJ, Wuthier RE. Studies on matrix vesicles isolated from chick epiphyseal cartilage. Association of pyrophosphatase and ATPase activities with alkaline phosphatase. Biochem Biophys Acta. 1975;391:51-50.

   Not in our library10.1016/0005-2744(75)90151-5

8. 8.

   Johnson KA, Hessle L, Vaingankar S, et al. Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1365-1377.

   Not in our library10.1152/ajpregu.2000.279.4.r1365

9. 9.

   Hessle L, Johnson KA, Anderson HC, et al. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci USA. 2002;99:9445-9449.

   Not in our library10.1073/pnas.142063399

10. 10.

    Murshed M, Harmey D, Millán JL, McKee MD, Karsenty G. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 2005;19:1093-1104.

    Not in our library10.1101/gad.1276205

11. 11.

    Terkeltaub R, Rosenbach M, Fong F, Goding J. Causal link between nucleotide pyrophosphohydrolase overactivity and increased intracellular inorganic pyrophosphate generation demonstrated by transfection of cultured fibroblasts and osteoblasts with plasma cell membrane glycoprotein-1. Arthritis Rheum. 1994;42:1986-1997.

    Not in our library10.1002/art.1780370624

12. 12.

    Terkeltaub RA. Inorganic pyrophosphate generation and disposition in pathophysiology. Am J Physiol Cell Physiol. 2001;281:C1-C11.

    Not in our library10.1152/ajpcell.2001.281.1.c1

13. 13.

    Hakim FT, Cranley R, Brown KS, Eanes ED, Harne L, Oppenheim JJ. Hereditary joint disorder in progressive ankylosis (ank/ank) mice. I. Association of calcium hydroxyapatite deposition with inflammatory arthropathy. Arthritis Rheum. 1984;27:1411-1420.

    Not in our library10.1002/art.1780271212

14. 14.

    Ho AM, Johnson MD, Kingsley DM. Role of mouse ank gene in control of tissue calcification and arthritis. Science. 2000;289:265-269.

    Not in our library10.1126/science.289.5477.265

15. 15.

    Millán JL. Mammalian Alkaline Phosphatases: From Biology to Applications in Medicine and Biotechnology. 2006;1-322.

    Not in our library

16. 16.

    Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev. 1994;15:439-461.

    Not in our library10.1210/edrv-15-4-439

17. 17.

    Whyte MP, Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW. Hypophosphatasia. The Metabolic and Molecular Bases of Inherited Disease. 2001;5313-5329.

    Not in our library

18. 18.

    Narisawa S, Fröhlander N, Millán JL. Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia. Dev Dyn. 1997;208:432-446.

    Not in our library10.1002/(sici)1097-0177(199703)208:3<432::aid-aja13>3.0.co;2-1

19. 19.

    Fedde KN, Blair L, Silverstein J, et al. Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res. 1999;14:2015-2026.

    Not in our library10.1359/jbmr.1999.14.12.2015

20. 20.

    Anderson HC, Hsu HHT, Morris DC, Fedde KN, Whyte MP. Matrix vesicles in osteomalacic hypophosphatasia bone contain apatite-like mineral crystals. Am J Pathol. 1997;151:1555-1561.

    Not in our library

21. 21.

    Anderson HC, Sipe JE, Hessle L, et al. Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase deficient mice. Am J Pathol. 2004;164:841-847.

    Not in our library10.1016/s0002-9440(10)63172-0

22. 22.

    Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R, Millán JL. Concerted regulation of inorganic pyrophosphate and osteopontin by Akp2, Enpp1, and Ank: An integrated model of the pathogenesis of mineralization disorders. Am J Pathol. 2004;164:1199-1209.

    Not in our library10.1016/s0002-9440(10)63208-7

23. 23.

    Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R, Millán JL. Elevated skeletal osteopontin levels contribute to the hypophosphatasia phenotype in Akp2−/− mice. J Bone Miner Res. 2006;21:1377-1386.

    Not in our library10.1359/jbmr.060619

24. 24.

    Addison WN, Azari F, Sorensen ES, Kaartinen MT, McKee MD. Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 2007;282:15872-15883.

    Not in our library10.1074/jbc.m701116200

25. 25.

    Houston B, Seawright E, Jefferies D, et al. Identification and cloning of a novel phosphatase expressed at high levels in differentiating growth plate chondrocytes. Biochim. Biophys Acta. 1999;1448:500-506.

    Not in our library10.1016/s0167-4889(98)00153-0

26. 26.

    Stewart AJ, Schmid R, Blindauer CA, Paisey SJ, Farquharson C. Comparative modelling of human PHOSPHO1 reveals a new group of phosphatases within the haloacid dehalogenase superfamily. Protein Eng. 2003;16:889-895.

    Not in our library10.1093/protein/gzg126

27. 27.

    Houston B, Stewart AJ, Farquharson C. PHOSPHO1-A novel phosphatase specifically expressed at sites of mineralization in bone and cartilage. Bone. 2004;34:629-637.

    Not in our library10.1016/j.bone.2003.12.023

28. 28.

    Roberts SJ, Stewart AJ, Sadler PJ, Farquharson C. Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities. Biochem J. 2004;382:59-65.

    Not in our library10.1042/bj20040511

29. 29.

    Stewart AJ, Roberts SJ, Seawright E, Davey MG, Fleming RH, Farquharson C. The presence of PHOSPHO1 in matrix vesicles and its developmental expression prior to skeletal mineralization. Bone. 2006;39:1000-1007.

    Not in our library10.1016/j.bone.2006.05.014

30. 30.

    Roberts S, Narisawa S, Harmey D, Millan JL, Farquharson C. Functional involvement of PHOSPHO1 in matrix vesicle-mediated skeletal mineralization. J Bone Miner Res. 2007;22:617-627.

    Not in our library10.1359/jbmr.070108

31. 31.

    Anderson HC, Harmey D, Camacho NP, et al. Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in TNAP/NPP1 double-deficient mice. Am J Pathol. 2005;166:1711-1720.

    Not in our library10.1016/s0002-9440(10)62481-9

32. 32.

    Millán JL, Narisawa S, Lemire I, et al. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008;23:777-787.

    Not in our library10.1359/jbmr.071213

33. 33.

    Narisawa S, Wennberg C, Millan JL. Abnormal vitamin B6 metabolism in alkaline phosphatase knock-out mice causes multiple abnormalities, but not the impaired bone mineralization. J Pathol. 2001;193:125-133.

    Not in our library10.1002/1096-9896(2000)9999:9999<::aid-path722>3.0.co;2-y

34. 34.

    Johnson K, Goding J, Van Etten D, et al. Linked deficiencies in extracellular PPi and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression. J Bone Miner Res. 2003;18:994-1004.

    Not in our library10.1359/jbmr.2003.18.6.994

35. 35.
    Kinetic analysis of substrate utilization by native and TNAP-, NPP1-, or PHOSPHO1-deficient matrix vesicles · 2010

    No notice
36. 36.

    Wolff J. 1892.

    Not in our library

37. 37.

    Frost HM. Mechanical determinants of bone modeling. Metab Bone Dis Relat Res. 1982;4:217-229.

    Not in our library10.1016/0221-8747(82)90031-5

38. 38.

    Motosuneya T, Asazuma T, Yasuoka H, Tsuji T, Fujikawa K. Severe kyphoscoliosis associated with osteomalacia. Spine J. 2006;6:587-590.

    Not in our library10.1016/j.spinee.2006.01.008

39. 39.

    Carter DR, Beaupré GS. Skeletal Function and Form: Mechanobiology of Skeletal Development, Ageing and Regeneration. 2001;20.

    Not in our library

40. 40.

    Kvam BJ, Pollesello P, Vittur F, Paoletti S. 31P NMR studies of resting zone cartilage from growth plate. Magn Reson Med. 1992;25:355-361.

    Not in our library10.1002/mrm.1910250215

Cited by papers we hold 2

• Alkaline Phosphatase, an Unconventional Immune Protein · 2017
  No notice
• Alkaline Phosphatase and Hypophosphatasia · 2015
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.