title: The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts.
abstract: Bone homeostasis is maintained by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation in the activity of the bone cells can lead to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. Kalirin is a novel GTP-exchange factor protein that has been shown to play a role in cytoskeletal remodeling and dendritic spine formation in neurons. We examined Kalirin expression in skeletal tissue and found that it was expressed in osteoclasts and osteoblasts. Furthermore, micro-CT analyses of the distal femur of global Kalirin knockout (Kal-KO) mice revealed significantly reduced trabecular and cortical bone parameters in Kal-KO mice, compared to WT mice, with significantly reduced bone mass in 8, 14 and 36week-old female Kal-KO mice. Male mice also exhibited a decrease in bone parameters but not to the level seen in female mice. Histomorphometric analyses also revealed decreased bone formation rate in 14week-old female Kal-KO mice, as well as decreased osteoblast number/bone surface and increased osteoclast surface/bone surface. Consistent with our in vivo findings, the bone resorbing activity and differentiation of Kal-KO osteoclasts was increased in vitro. Although alkaline phosphatase activity by Kal-KO osteoblasts was increased in vitro, Kal-KO osteoblasts showed decreased mineralizing activity, as well as decreased secretion of OPG, which was inversely correlated with ERK activity. Taken together, our findings suggest that deletion of Kalirin directly affects osteoclast and osteoblast activity, leading to decreased OPG secretion by osteoblasts which is likely to alter the RANKL/OPG ratio and promote osteoclastogenesis. Therefore, Kalirin may play a role in paracrine and/or endocrine signaling events that control skeletal bone remodeling and the maintenance of bone mass.
authors.affiliation: Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, IN, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, IN, USA.
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Eleniste
authors.affiliation: Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, IN, USA.
authors.forename: Kornchanok
authors.initials: K
authors.lastname: Wayakanon
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Mandela
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.affiliation: Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, IN, USA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: abruzzan@iu.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: Bruzzaniti
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D016723:Bone Remodeling; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D002452:Cell Count; D002454:Cell Differentiation; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D020662:Guanine Nucleotide Exchange Factors; C548820:KALRN protein, mouse
keywords: GTP-exchange factor; Osteoprotegerin, bone remodeling; Receptor activator of nuclear factor κb ligand