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Molecular and Cellular Biology, June 2005, p. 5253-5269, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5253-5269.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Rab3D Regulates a Novel Vesicular Trafficking Pathway That Is Required for Osteoclastic Bone Resorption{dagger}

Nathan J. Pavlos,1 Jiake Xu,1 Dietmar Riedel,3 Joyce S. G. Yeoh,1,{ddagger} Steven L. Teitelbaum,4 John M. Papadimitriou,2 Reinhard Jahn,3 F. Patrick Ross,4* and Ming H. Zheng1*

Units of Orthopaedics,1 Pathology, School of Surgery and Pathology, University of Western Australia, QEII Medical Centre, Perth, Western Australia, Australia,2 Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen 37077, Germany,3 Department of Pathology, Washington University School of Medicine, St. Louis, Missouri4

Received 6 December 2004/ Returned for modification 10 February 2005/ Accepted 4 March 2005

Rab3 proteins are a subfamily of GTPases, known to mediate membrane transport in eukaryotic cells and play a role in exocytosis. Our data indicate that Rab3D is the major Rab3 species expressed in osteoclasts. To investigate the role of Rab3D in osteoclast physiology we examined the skeletal architecture of Rab3D-deficient mice and found an osteosclerotic phenotype. Although basal osteoclast number in null animals is normal the total eroded surface is significantly reduced, suggesting that the resorptive defect is due to attenuated osteoclast activity. Consistent with this hypothesis, ultrastructural analysis reveals that Rab3D–/– osteoclasts exhibit irregular ruffled borders. Furthermore, while overexpression of wild-type, constitutively active, or prenylation-deficient Rab3D has no significant effects, overexpression of GTP-binding-deficient Rab3D impairs bone resorption in vitro. Finally, subcellular localization studies reveal that, unlike wild-type or constitutively active Rab3D, which associate with a nonendosomal/lysosomal subset of post-trans-Golgi network (TGN) vesicles, inactive Rab3D localizes to the TGN and inhibits biogenesis of Rab3D-bearing vesicles. Collectively, our data suggest that Rab3D modulates a post-TGN trafficking step that is required for osteoclastic bone resorption.

* Corresponding author. Mailing address for Ming H. Zheng: Unit of Orthopaedics, School of Surgery and Pathology, University of Western Australia, 2nd Floor "M" Block, QEII Medical Centre, Nedlands, Perth, Western Australia 6009, Australia. Phone: 61 (8) 9346-4050. Fax: 61 (8) 9346-3210. E-mail: zheng{at}cyllene.uwa.edu.au. Mailing address for F. Patrick Ross: Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: (314) 454-8079. Fax: (314) 454-5505. E-mail:rossf{at}wustl.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Stem Cell Biology, University of Groningen, University Hospital Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.

Molecular and Cellular Biology, June 2005, p. 5253-5269, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5253-5269.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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