Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect

Martin O. Bergo, Bryant Gavino, Jed Ross, Walter K. Schmidt, Christine Hong, Lonnie V. Kendall, Andreas Mohr, Margarita Meta, Harry Genant, Yebin Jiang, Erik R Wisner, Nicholas Van Bruggen, Richard A D Carano, Susan Michaelis, Stephen M Griffey, Stephen G. Young

Research output: Contribution to journalArticle

296 Scopus citations

Abstract

Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum. Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24-/-) have indicated a role for Zmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologic consequences of Zmpste24 deficiency in mice. Zmpste24-/- mice gain weight slowly, appear malnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes are significantly reduced in Zmpste24-/- mice. Zmpste24-/- mice also manifested muscle weakness in the lower and upper extremities, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase lcmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24-/- mice can be reasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a broader role for Zmpste24 in mammalian biology.

Original languageEnglish (US)
Pages (from-to)13049-13054
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number20
DOIs
StatePublished - Oct 1 2002

    Fingerprint

Keywords

  • Brittle bones
  • CAAX motif
  • Knockout mice
  • Metalloproteinase

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Bergo, M. O., Gavino, B., Ross, J., Schmidt, W. K., Hong, C., Kendall, L. V., Mohr, A., Meta, M., Genant, H., Jiang, Y., Wisner, E. R., Van Bruggen, N., Carano, R. A. D., Michaelis, S., Griffey, S. M., & Young, S. G. (2002). Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proceedings of the National Academy of Sciences of the United States of America, 99(20), 13049-13054. https://doi.org/10.1073/pnas.192460799