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Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity

Abstract

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.

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Figure 1: Pleiotropism of SPENCD.
Figure 2: Mutations in ACP5 and their effect on TRAP activity.
Figure 3: Osteopontin deregulation in SPENCD.
Figure 4: TRAP-deficient dendritic cells secrete Th1-polarizing cytokines and show enhanced T cell allostimulatory activity.
Figure 5: Variable serum cytokine patterns in individuals with SPENCD.

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References

  1. Walker, B.S., Lemon, H.M., Davison, M.M. & Schwartz, M.K. Acid phosphatases: a review. Am. J. Clin. Pathol. 24, 807–837 (1954).

    CAS  Article  Google Scholar 

  2. Janckila, A.J. & Yam, L.T. Biology and clinical significance of tartrate-resistant acid phosphatases: new perspectives on an old enzyme. Calcif. Tissue Int. 85, 465–483 (2009).

    CAS  Article  Google Scholar 

  3. Oddie, G.W. et al. Structure, function, and regulation of tartrate-resistant acid phosphatase. Bone 27, 575–584 (2000).

    CAS  Article  Google Scholar 

  4. Hayman, A.R. Tartrate-resistant acid phosphatase (TRAP) and the osteoclast/immune cell dichotomy. Autoimmunity 41, 218–223 (2008).

    CAS  Article  Google Scholar 

  5. Hayman, A.R. et al. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development 122, 3151–3162 (1996).

    CAS  PubMed  Google Scholar 

  6. Bune, A.J., Hayman, A.R., Evans, M.J. & Cox, T.M. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disordered macrophage inflammatory responses and reduced clearance of the pathogen, Staphylococcus aureus. Immunology 102, 103–113 (2001).

    CAS  Article  Google Scholar 

  7. Esfandiari, E. et al. TRACP influences Th1 pathways by affecting dendritic cell function. J. Bone Miner. Res. 21, 1367–1376 (2006).

    CAS  Article  Google Scholar 

  8. Schorr, S., Legum, C. & Ochshorn, M. Spondyloenchondrodysplasia. Enchondromatosis with severe platyspondyly in two brothers. Radiology 118, 133–139 (1976).

    CAS  Article  Google Scholar 

  9. Menger, H., Kruse, K. & Spranger, J. Spondyloenchondrodysplasia. J. Med. Genet. 26, 93–99 (1989).

    CAS  Article  Google Scholar 

  10. Frydman, M. et al. Possible heterogeneity in spondyloenchondrodysplasia: quadriparesis, basal ganglia calcifications, and chondrocyte inclusions. Am. J. Med. Genet. 36, 279–284 (1990).

    CAS  Article  Google Scholar 

  11. Renella, R. et al. Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: clinical and radiographic delineation of a pleiotropic disorder. Am. J. Med. Genet. A. 140, 541–550 (2006).

    Article  Google Scholar 

  12. Schaerer, K. Ueber einen Fall von kindlichem Lupus erythematodes generalisatus mit eigenartigen Knochenveraenderungen. Helv. Paediatr. Acta 13, 40–68 (1958).

    Google Scholar 

  13. Nakanishi, M., Yoh, K., Uchida, K., Maruo, S. & Matsuoka, A. Improved method for measuring tartrate-resistant acid phosphatase activity in serum. Clin. Chem. 44, 221–225 (1998).

    CAS  PubMed  Google Scholar 

  14. Halleen, J.M. et al. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J. Bone Miner. Res. 15, 1337–1345 (2000).

    CAS  Article  Google Scholar 

  15. Hayman, A.R., Macary, P., Lehner, P.J. & Cox, T.M. Tartrate-resistant acid phosphatase (Acp 5): identification in diverse human tissues and dendritic cells. J. Histochem. Cytochem. 49, 675–684 (2001).

    CAS  Article  Google Scholar 

  16. Andersson, G. et al. TRACP as an osteopontin phosphatase. J. Bone Miner. Res. 18, 1912–1915 (2003).

    CAS  Article  Google Scholar 

  17. Ek-Rylander, B., Flores, M., Wendel, M., Heinegard, D. & Andersson, G. Dephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase. Modulation of osteoclast adhesion in vitro. J. Biol. Chem. 269, 14853–14856 (1994).

    CAS  PubMed  Google Scholar 

  18. Suter, A. et al. Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice. Development 128, 4899–4910 (2001).

    CAS  PubMed  Google Scholar 

  19. Kazanecki, C.C., Uzwiak, D.J. & Denhardt, D.T. Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J. Cell. Biochem. 102, 912–924 (2007).

    CAS  Article  Google Scholar 

  20. Senger, D.R., Perruzzi, C.A., Papadopoulos-Sergiou, A. & Van de Water, L. Adhesive properties of osteopontin: regulation by a naturally occurring thrombin-cleavage in close proximity to the GRGDS cell-binding domain. Mol. Biol. Cell 5, 565–574 (1994).

    CAS  Article  Google Scholar 

  21. Yokosaki, Y. et al. The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin. J. Biol. Chem. 274, 36328–36334 (1999).

    CAS  Article  Google Scholar 

  22. Ashkar, S. et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287, 860–864 (2000).

    CAS  Article  Google Scholar 

  23. Kawamura, K. et al. Differentiation, maturation, and survival of dendritic cells by osteopontin regulation. Clin. Diagn. Lab. Immunol. 12, 206–212 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Burdo, T.H., Wood, M.R. & Fox, H.S. Osteopontin prevents monocyte recirculation and apoptosis. J. Leukoc. Biol. 81, 1504–1511 (2007).

    CAS  Article  Google Scholar 

  25. Shinohara, M.L., Kim, J.H., Garcia, V.A. & Cantor, H. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity 29, 68–78 (2008).

    CAS  Article  Google Scholar 

  26. Murugaiyan, G., Mittal, A. & Weiner, H.L. Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J. Immunol. 181, 7480–7488 (2008).

    CAS  Article  Google Scholar 

  27. Cantor, H. & Shinohara, M.L. Regulation of T-helper-cell lineage development by osteopontin: the inside story. Nat. Rev. Immunol. 9, 137–141 (2009).

    CAS  Article  Google Scholar 

  28. Shinohara, M.L. et al. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat. Immunol. 7, 498–506 (2006).

    CAS  Article  Google Scholar 

  29. Sun, P. et al. Acid phosphatase 5 is responsible for removing the mannose 6-phosphate recognition marker from lysosomal proteins. Proc. Natl. Acad. Sci. USA 105, 16590–16595 (2008).

    CAS  Article  Google Scholar 

  30. Räisänen, S.R., Halleen, J., Parikka, V. & Vaananen, H.K. Tartrate-resistant acid phosphatase facilitates hydroxyl radical formation and colocalizes with phagocytosed Staphylococcus aureus in alveolar macrophages. Biochem. Biophys. Res. Commun. 288, 142–150 (2001).

    Article  Google Scholar 

  31. Raisanen, S.R. et al. Macrophages overexpressing tartrate-resistant acid phosphatase show altered profile of free radical production and enhanced capacity of bacterial killing. Biochem. Biophys. Res. Commun. 331, 120–126 (2005).

    Article  Google Scholar 

  32. Kaija, H. et al. Phosphatase and oxygen radical-generating activities of mammalian purple acid phosphatase are functionally independent. Biochem. Biophys. Res. Commun. 292, 128–132 (2002).

    CAS  Article  Google Scholar 

  33. Weber, G.F. et al. Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation. J. Leukoc. Biol. 72, 752–761 (2002).

    CAS  PubMed  Google Scholar 

  34. Steinman, L. A molecular trio in relapse and remission in multiple sclerosis. Nat. Rev. Immunol. 9, 440–447 (2009).

    CAS  Article  Google Scholar 

  35. Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).

    CAS  Article  Google Scholar 

  36. Iizuka, J. et al. Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies. Lab. Invest. 78, 1523–1533 (1998).

    CAS  PubMed  Google Scholar 

  37. Wong, C.K., Lit, L.C., Tam, L.S., Li, E.K. & Lam, C.W. Elevation of plasma osteopontin concentration is correlated with disease activity in patients with systemic lupus erythematosus. Rheumatology (Oxford) 44, 602–606 (2005).

    CAS  Article  Google Scholar 

  38. Stromnes, I.M. & Goverman, J.M. Osteopontin-induced survival of T cells. Nat. Immunol. 8, 19–20 (2007).

    CAS  Article  Google Scholar 

  39. Renkl, A.C. et al. Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype. Blood 106, 946–955 (2005).

    CAS  Article  Google Scholar 

  40. Hur, E.M. et al. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat. Immunol. 8, 74–83 (2007).

    CAS  Article  Google Scholar 

  41. Vogt, M.H., Lopatinskaya, L., Smits, M., Polman, C.H. & Nagelkerken, L. Elevated osteopontin levels in active relapsing-remitting multiple sclerosis. Ann. Neurol. 53, 819–822 (2003).

    CAS  Article  Google Scholar 

  42. D'Alfonso, S. et al. Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 52, 539–547 (2005).

    CAS  Article  Google Scholar 

  43. Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    CAS  Article  Google Scholar 

  44. Gudbjartsson, D.F., Thorvaldsson, T., Kong, A., Gunnarsson, G. & Ingolfsdottir, A. Allegro version 2. Nat. Genet. 37, 1015–1016 (2005).

    CAS  Article  Google Scholar 

  45. Sträter, N. et al. Crystal structures of recombinant human purple Acid phosphatase with and without an inhibitory conformation of the repression loop. J. Mol. Biol. 351, 233–246 (2005).

    Article  Google Scholar 

  46. Hellemans, J., Mortier, G., De Paepe, A., Speleman, F. & Vandesompele, J. qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 8, R19 (2007).

    Article  Google Scholar 

  47. Hayman, A.R., Warburton, M.J., Pringle, J.A., Coles, B. & Chambers, T.J. Purification and characterization of a tartrate-resistant acid phosphatase from human osteoclastomas. Biochem. J. 261, 601–609 (1989).

    CAS  Article  Google Scholar 

  48. Lausch, E. et al. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am. J. Hum. Genet. 85, 168–178 (2009).

    CAS  Article  Google Scholar 

  49. Rosenthal, A.K., Gohr, C.M., Uzuki, M. & Masuda, I. Osteopontin promotes pathologic mineralization in articular cartilage. Matrix Biol. 26, 96–105 (2007).

    CAS  Article  Google Scholar 

  50. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank our cases and their families for participation in this study. We are also grateful to T. Velten and to the Lausch/Zabel lab for excellent technical assistance and to M. Osawa and H. Katumori, Tokyo, for clinical information. S. Ehl and his group at the Centre for Chronic Immunodeficiency in Freiburg were most helpful in discussing immunological aspects and experimental strategies. This work was made possible by continuous grant support from the Deutsche Forschungsgemeinschaft to E.L. and B.Z. (La 1381/1-3). B.Z. is also supported by the German Bundesministerium für Bildung und Forschung (SKELNET project), and A.S.-F. is supported by the Leenaards Foundation (Lausanne, Switzerland). The paper is dedicated to Céline and Sinai.

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E.L. and A.S.-F. conceived and initiated the project and E.L. designed functional studies. B.Z., A.S.-F. and E.L. secured financial support. Y.A., C.D.L., C.A.H., P.M., G.N., M.M., Y.H., S. Tenoutasse, A.K., R.F.M.R., S.L.U., R.R., L.B., J.S., B.Z., E.L. and A.S.-F. identified cases of SPENCD, provided clinical information and collected biologic materials. S.U., R.R., J.S., E.L. and A.S.-F. assessed the clinical and radiographic data for inclusion in the study. A.S.-F., E.L. and A.J. performed linkage and mutation analysis. E.L. performed biochemical analyses and statistical evaluation. E.L., M.B. and S. Trojandt performed the expression studies as well as the functional and immunological studies with dendritic cells. B.Z., S.U. and R.R. discussed the ongoing experiments with E.L. and A.S.-F. Finally, E.L., S.U., B.Z. and A.S.-F. wrote the manuscript.

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Correspondence to Andrea Superti-Furga.

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Lausch, E., Janecke, A., Bros, M. et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 43, 132–137 (2011). https://doi.org/10.1038/ng.749

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