Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo.
Rac1 and Rac2 are thought to have important roles in osteoclasts. Therefore, mice with deletion of both Rac1 and Rac2 in mature osteoclasts (DKO) were generated by crossing Rac1(flox/flox) mice with mice expressing Cre in the cathepsin K locus and then mating these animals with Rac2(-/-) mice. DKO mice had markedly impaired tooth eruption. Bone mineral density (BMD) was increased 21% to 33% in 4- to 6-week-old DKO mice at all sites when measured by dual-energy X-ray absorptiometry (DXA) and serum cross-linked C-telopeptide (CTx) was reduced by 52%. The amount of metaphyseal trabecular bone was markedly increased in DKO mice, but the cortices were very thin. Spinal trabecular bone mass was increased. Histomorphometry revealed significant reductions in both osteoclast and osteoblast number and function in 4- to 6-week-old DKO animals. In 14- to 16-week-old animals, osteoclast number was increased, although bone density was further increased. DKO osteoclasts had severely impaired actin ring formation, an impaired ability to generate acid, and reduced resorptive activity in vitro. In addition, their life span ex vivo was reduced. DKO osteoblasts expressed normal differentiation markers except for the expression of osterix, which was reduced. The DKO osteoblasts mineralized normally in vitro, indicating that the in vivo defect in osteoblast function was not cell autonomous. Confocal imaging demonstrated focal disruption of the osteocytic dendritic network in DKO cortical bone. Despite these changes, DKO animals had a normal response to treatment with once-daily parathyroid hormone (PTH). We conclude that Rac1 and Rac2 have critical roles in skeletal metabolism.
Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Meiling
M
Zhu
Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Ben-Hua
BH
Sun
Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Katarzyna
K
Saar
Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Christine
C
Simpson
Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT, USA.
Nancy
N
Troiano
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, Kansas City, MO, USA.
Sarah L
SL
Dallas
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, Kansas City, MO, USA.
LeAnn M
LM
Tiede-Lewis
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Erin
E
Nevius
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
João P
JP
Pereira
Department of Internal Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Health Care System, Little Rock, AR, USA.
Robert S
RS
Weinstein
Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT, USA.
Steven M
SM
Tommasini
Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Karl L
KL
Insogna
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002452:Cell Count; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; 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
OSTEOCLASTS; OSTEOCYTES; RAC1; RAC2