Deleting Rac1 improves vertebral bone quality and resistance to fracture in a murine ovariectomy model.
CONCLUSIONS
The roles of Rac1 and Rac2 in regulating osteoclast-mediated bone quality in postmenopausal osteoporosis were evaluated using an ovariectomized murine model. Animals' bone composition and architecture were evaluated. Our results demonstrate that the deletion of Rac1 increases vertebral bone quality compared to wild-type bones in an ovariectomized model.


BACKGROUND
To determine the roles of the Rho family small GTPases Rac1 and Rac2 in regulating osteoclast-mediated bone quality in a model of postmenopausal osteoporosis.


METHODS
Twelve-month-old female mice from three genotypes-wild type (WT), Rac1 null (LysM.Rac1 KO), and Rac2 null (Rac2KO)--were studied in control and ovariectomized groups (mice previously ovariectomized at 4 months of age). Animals were sacrificed at 12 months of age, and the femora and vertebrae were harvested for mechanical testing, bone densitometry, micro-computed tomography, and histomorphometric analyses to evaluate bone mineralization and architecture. The results were compared between groups using ANOVA and LSD post-hoc tests.


RESULTS
We observed that LysM.Rac1 KO mice showed higher vertebral bone mineral density compared to WT in both control and ovariectomized groups. Consistent with this finding, LysM.Rac1 KO vertebrae showed increased resistance to fracture and increased trabecular connectivity compared to WT in both groups. Micro-CT analysis revealed that Rac2KO ovariectomized vertebrae have more trabecular bone compared to WT and LysM.Rac1 KO, but this did not translate into increased fracture resistance.


CONCLUSIONS
Our results demonstrate that the deletion of Rac1 increases vertebral bone quality compared to WT bones in a postmenopausal osteoporosis model.
Magalhaes
J K R S
JK
CIHR Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Fitzgerald Building-150 College Street, Room 221, Toronto, ON, Canada M5S 3E2.
Grynpas
M D
MD
Willett
T L
TL
Glogauer
M
M
D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000503:physiopathology; D017353:Gene Deletion; D006801:Humans; D008159:Lumbar Vertebrae / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015663:Osteoporosis, Postmenopausal / Q000235:genetics / Q000503:physiopathology*; D058866:Osteoporotic Fractures / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D010052:Ovariectomy; D013314:Stress, Mechanical; D055114:X-Ray Microtomography; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
D009479:Neuropeptides; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse