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J Bone Miner Res. 2016 Apr;31(4):864-73. doi: 10.1002/jbmr.2733. Epub 2015 Nov 18.

Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo.

Author information

1
Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, CT, USA.
2
Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT, USA.
3
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, Kansas City, MO, USA.
4
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
5
Department of Internal Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Health Care System, Little Rock, AR, USA.

Abstract

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.

KEYWORDS:

OSTEOCLASTS; OSTEOCYTES; RAC1; RAC2

PMID:
26496249
PMCID:
PMC4826801
DOI:
10.1002/jbmr.2733
[Indexed for MEDLINE]
Free PMC Article

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