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Rac deletion in osteoclasts causes severe osteopetrosis.
- Source :
-
Journal of cell science [J Cell Sci] 2011 Nov 15; Vol. 124 (Pt 22), pp. 3811-21. Date of Electronic Publication: 2011 Nov 23. - Publication Year :
- 2011
-
Abstract
- Cdc42 mediates bone resorption principally by stimulating osteoclastogenesis. Whether its sister GTPase, Rac, meaningfully impacts upon the osteoclast and, if so, by what means, is unclear. We find that whereas deletion of Rac1 or Rac2 alone has no effect, variable reduction of Rac1 in osteoclastic cells of Rac2(-/-) mice causes severe osteopetrosis. Osteoclasts lacking Rac1 and Rac2 in combination (Rac double-knockout, RacDKO), fail to effectively resorb bone. By contrast, osteoclasts are abundant in RacDKO osteopetrotic mice and, unlike those deficient in Cdc42, express the maturation markers of the cells normally. Hence, the osteopetrotic lesion of RacDKO mice largely reflects impaired function, and not arrested differentiation, of the resorptive polykaryon. The dysfunction of RacDKO osteoclasts represents failed cytoskeleton organization as evidenced by reduced motility of the cells and their inability to spread or generate the key resorptive organelles (i.e. actin rings and ruffled borders), which is accompanied by abnormal Arp3 distribution. The cytoskeleton-organizing capacity of Rac1 is mediated through its 20-amino-acid effector domain. Thus, Rac1 and Rac2 are mutually compensatory. Unlike Cdc42 deficiency, their combined absence does not impact upon differentiation but promotes severe osteopetrosis by dysregulating the osteoclast cytoskeleton.
- Subjects :
- Animals
Bone Resorption
Cells, Cultured
Cytoskeleton genetics
Cytoskeleton metabolism
Disease Models, Animal
Female
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteopetrosis physiopathology
rac GTP-Binding Proteins metabolism
rac1 GTP-Binding Protein metabolism
RAC2 GTP-Binding Protein
Gene Deletion
Osteoclasts enzymology
Osteopetrosis enzymology
Osteopetrosis genetics
rac GTP-Binding Proteins genetics
rac1 GTP-Binding Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9137
- Volume :
- 124
- Issue :
- Pt 22
- Database :
- MEDLINE
- Journal :
- Journal of cell science
- Publication Type :
- Academic Journal
- Accession number :
- 22114304
- Full Text :
- https://doi.org/10.1242/jcs.086280