, Volume 39, Issue 2, pp 104–112 | Cite as

Loss-of-function of SHARPIN causes an osteopenic phenotype in mice

  • Tian Xia
  • Yanhua Liang
  • Junrong Ma
  • Mi Li
  • Meng Gong
  • Xijie Yu
Original Article


SHARPIN is a novel protein thought to interact with SHANK family and is widely expressed in multiple tissues/cells, including osteoblasts and osteoclasts. Loss-of-function of Sharpin develops the chronic proliferative dermatitis mutation (CPDM) in mice as well as a severe inflammation in other organs. The actual function of SHARPIN is poorly understood. Our aim was to determine the functional roles of SHARPIN in bone metabolism by using CPDM mice. The skeletal phenotypes were determined by peripheral quantitative computed tomography, micro-computed tomography, and quantitative real-time RT-PCR, the cellular functions of osteoblasts and osteoclasts were investigated by ex vivo cell culture. Compared to wild-type controls, CPDM mice demonstrated significantly lower total and cortical bone mineral content and bone mineral density, trabecular and cortical bone volume, and trabecular number. The mRNA expression of Runx2, osterix, type I collagen, and osteocalcin was significantly lower in the bone from CPDM mice. Osteoclasts and osteoblasts from CPDM mice were functionally defective. Our result suggests that SHARPIN plays important regulating roles in bone metabolism. These functional roles may either come from systemic chronic inflammatory or directly signaling pathway within bone cells.


SHARPIN Osteopenia Osteoblasts Osteoclasts 



This work was support by a grant to Dr. Xijie Yu from National Natural Science Foundation of China (No. 30872632).


  1. 1.
    Y. Daigo, I. Takayama, S.M. Ward, K.M. Sanders, M.A. Fujino, Novel human and mouse genes encoding a shank-interacting protein and its upregulation in gastric fundus of W/WV mouse. J. Gastroenterol. Hepatol. 18, 712–718 (2003)PubMedCrossRefGoogle Scholar
  2. 2.
    A. Marchler-Bauer, J.B. Anderson, M.K. Derbyshire, C. DeWeese-Scott, N.R. Gonzales, M. Gwadz, L. Hao, S. He, D.I. Hurwitz, J.D. Jackson, Z. Ke, D. Krylov, C.J. Lanczycki, C.A. Liebert, C. Liu, F. Lu, S. Lu, G.H. Marchler, M. Mullokandov, J.S. Song, N. Thanki, R.A. Yamashita, J.J. Yin, D. Zhang, S.H. Bryant, CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res. 35, D237–D240 (2007)PubMedCrossRefGoogle Scholar
  3. 3.
    S. Lim, C. Sala, J. Yoon, S. Park, S. Kuroda, M. Sheng, E. Kim, Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Mol. Cell Neurosci. 17, 385–397 (2001)PubMedCrossRefGoogle Scholar
  4. 4.
    J. Jung, J.M. Kim, B. Park, Y. Cheon, B. Lee, S.H. Choo, S.S. Koh, S. Lee, Newly identified tumor-associated role of human Sharpin. Mol. Cell. Biochem. 340, 161–167 (2010)PubMedCrossRefGoogle Scholar
  5. 5.
    R.E. Seymour, M.G. Hasham, G.A. Cox, L.D. Shultz, H. Hogenesch, D.C. Roopenian, J.P. Sundberg, Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun. 8, 416–421 (2007)PubMedCrossRefGoogle Scholar
  6. 6.
    H. HogenEsch, M.J. Gijbels, E. Offerman, J. van Hooft, D.W. van Bekkum, C. Zurcher, A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice. Am. J. Pathol. 143, 972–982 (1993)PubMedGoogle Scholar
  7. 7.
    H.I. Gallardo Torres, M.J. Gijbels, H. HegnEsch, G. Kraal, Chronic proliferative dermatitis in mice: neutrophil-endothelium interactions and the role of adhesion molecules. Pathobiology 63, 341–347 (1995)PubMedCrossRefGoogle Scholar
  8. 8.
    M.J. Gijbels, H. HogenEsch, B. Blauw, P. Roholl, C. Zurcher, Ultrastructure of epidermis of mice with chronic proliferative dermatitis. Ultrastruct. Pathol. 19, 107–111 (1995)PubMedCrossRefGoogle Scholar
  9. 9.
    M.J. Gijbels, C. Zurcher, G. Kraal, G.R. Elliott, H. HogenEsch, G. Schijff, H.F. Savelkoul, P.L. Bruijnzeel, Pathogenesis of skin lesions in mice with chronic proliferative dermatitis (cpdm/cpdm). Am. J. Pathol. 148, 941–950 (1996)PubMedGoogle Scholar
  10. 10.
    H. HogenEsch, D. Boggess, J.P. Sundberg, Changes in keratin and filaggrin expression in the skin of CPDM mutant mice. Pathobiology 67, 45–50 (1999)PubMedCrossRefGoogle Scholar
  11. 11.
    H. HogenEsch, S. Janke, D. Boggess, J.P. Sundberg, Absence of Peyer’s patches and abnormal lymphoid architecture in chronic proliferative dermatitis (cpdm/cpdm) mice. J. Immunol. 162, 3890–3896 (1999)PubMedGoogle Scholar
  12. 12.
    R. Hardy, M.S. Cooper, Bone loss in inflammatory disorders. J. Endocrinol. 201, 309–320 (2009)PubMedCrossRefGoogle Scholar
  13. 13.
    T.M. Schroeder, E.D. Jensen, J.J. Westendorf, Runx2: a master organizer of gene transcription in developing and maturing osteoblasts. Birth Defects Res. C Embryo Today 75, 213–225 (2005)PubMedCrossRefGoogle Scholar
  14. 14.
    K. Nakashima, X. Zhou, G. Kunkel, Z. Zhang, J.M. Deng, R.R. Behringer, B. de Crombrugghe, The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002)PubMedCrossRefGoogle Scholar
  15. 15.
    C. Desbois, G. Karsenty, Osteocalcin cluster: implications for functional studies. J. Cell Biochem. 57, 379–383 (1995)PubMedCrossRefGoogle Scholar
  16. 16.
    J. Lorenzo, M. Horowitz, Y. Choi, Osteoimmunology: interactions of the bone and immune system. Endocr. Rev. 29, 403–440 (2008)PubMedCrossRefGoogle Scholar
  17. 17.
    L. Gilbert, X. He, P. Farmer, S. Boden, M. Kozlowski, J. Rubin, M.S. Nanes, Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141, 3956–3964 (2000)PubMedCrossRefGoogle Scholar
  18. 18.
    M.L. Renninger, R. Seymour, J.W. Lillard Jr., J.P. Sundberg, H. HogenEsch, Increased expression of chemokines in the skin of chronic proliferative dermatitis mutant mice. Exp. Dermatol. 14, 906–913 (2005)PubMedCrossRefGoogle Scholar
  19. 19.
    I.M. Haeck, N.A. Hamdy, L. Timmer-de Mik, E.G. Lentjes, H.J. Verhaar, M.J. Knol, M.S. de Bruin-Weller, C.A. Bruijnzeel-Koomen, Low bone mineral density in adult patients with moderate to severe atopic dermatitis. Br. J. Dermatol. 161, 1248–1254 (2009)PubMedCrossRefGoogle Scholar
  20. 20.
    A. Meixner, R. Zenz, H.B. Schonthaler, L. Kenner, H. Scheuch, J.M. Penninger, E.F. Wagner, Epidermal JunB represses G-CSF transcription and affects haematopoiesis and bone formation. Nat. Cell Biol. 10, 1003–1011 (2008)PubMedCrossRefGoogle Scholar
  21. 21.
    J.E. Onyia, B. Miller, J. Hulman, J. Liang, R. Galvin, C. Frolik, S. Chandrasekhar, A.K. Harvey, J. Bidwell, J. Herring, J.M. Hock, Proliferating cells in the primary spongiosa express osteoblastic phenotype in vitro. Bone 20, 93–100 (1997)PubMedCrossRefGoogle Scholar
  22. 22.
    K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time qPCR and the 2(-Delta Delta C(T)) method. Methods 25, 402–408 (2001)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Tian Xia
    • 1
  • Yanhua Liang
    • 3
  • Junrong Ma
    • 1
  • Mi Li
    • 1
  • Meng Gong
    • 2
  • Xijie Yu
    • 1
    • 2
  1. 1.Laboratory of Endocrinology and Metabolism, West China HospitalSichuan UniversityChengduPeople’s Republic of China
  2. 2.Maine Institute for Human Genetics & HealthBangorUSA
  3. 3.Department of DermatologyYale University School of MedicineNew HavenUSA

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