Martin O. Bergö1,2,3,4, Bryant J. Gavino3,4, J K Ross4, Walter K. Schmidt4, Christine Hong3,4, Lonnie V. Kendall4, Andreas Mohr4, Margarita Meta4, Harry K. Genant4, Yebin Jiang4, Erik R. Wisner4, Nicholas van Bruggen4, Richard A.D. Carano4, Susan Michaelis4, Stephen M. Griffey5,2,4, Stephen G. Young1,2,3,4
1Cardiovascular Research Institute, University of California, San Francisco, CA 94143
2Department of Medicine, University of California, and the Medical Services, San Francisco General Hospital, San Francisco, CA 94110
3Department of Radiology, University of California, San Francisco, CA 94143; and
4Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141-9100; Cardiovascular Research Institute, University of California, San Francisco, CA 94143; Genentech, Incorporated, South San Francisco, CA 94080; Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Comparative Pathology Laboratory, University of California, Davis, CA 95616; Department of Radiology, University of California, San Francisco, CA 94143; and...
5Comparative Pathology Laboratory, University of California, Davis, CA 95616;
Tóm tắt
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 Icmt 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.
