title: Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss.
abstract: Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca(2+) oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12(fl/fl) cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss.
authors.affiliation: Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yuan
authors.affiliation: USDA Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Li
authors.affiliation: Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.|Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA.
authors.forename: F
authors.initials: F
authors.lastname: Scannapieco
authors.affiliation: Department of Stomatology, The Fourth Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning 110032, China.
authors.forename: X
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Medicine, Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Oursler
authors.affiliation: Department of Orthopedics, Center for Musculoskeletal Research, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Experimental Medicine, The Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Vacher
authors.affiliation: Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: D
authors.initials: D
authors.lastname: Olson
authors.affiliation: Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.|Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016723:Bone Remodeling; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D039481:CD11b Antigen; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D020710:RGS Proteins; C508173:RGS12 protein, mouse; D002118:Calcium