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Title: Regulators of G protein signaling 12 (Rgs12) promotes osteoclastogenesis in bone remodeling and pathologic bone loss

Author
item YUAN, XUE - State University Of New York (SUNY)
item Cao, Jay
item LIU, TONGJUN - State University Of New York (SUNY)
item LI, YI-PING - University Of Alabama
item SCANNAPIECO, FRANK - State University Of New York (SUNY)
item HE, XIAONING - China Medical University
item OURSLER, MERRY - Mayo Clinic
item ZHANG, XINPING - University Of Rochester
item VACHER, JEAN - University Of Montreal
item LI, CHUNYI - State University Of New York (SUNY)
item YANG, SHUYING - State University Of New York (SUNY)
item OLSON OLSON, DOUGLAS - New York University

Submitted to: Cell Death and Differentiation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/18/2015
Publication Date: 4/24/2015
Publication URL: http://handle.nal.usda.gov/10113/61234
Citation: Yuan, X., Cao, J.J., Liu, T., Li, Y., Scannapieco, F., He, X., Oursler, M.J., Zhang, X., Vacher, J., Li, C., Yang, S., Olson Olson, D. 2015. Regulators of G protein signaling 12 (Rgs12) promotes osteoclastogenesis in bone remodeling and pathologic bone loss. Cell Death and Differentiation. Available: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd201545a.html.

Interpretive Summary: Bone mass is regulated by the balance between bone forming cells, osteoblasts, and bone resorbing cells, osteoclasts. In osteoporosis condition, the balance shifts towards increased osteoclast activity. Regulator of G-protein signaling 12 (Rgs) has been found to play an important role in calcium signaling and osteoclast differentiation. Using a conditional Rgs-12 knockout mouse model, we demonstrated that Rgs-12 deficiency resulted in increased bone mass and decreased osteoclast differentiation, and function, and impaired calcium oscillations. Specific deletion of Rgs-12 in the osteoclast precursor cells inhibited osteoclastogenesis induced by ovariectomy. Our results demonstrate that Rgs-12 is a key regulator of bone resorption and can be used as a potential therapeutic target for osteoporosis treatment.

Technical Abstract: Calcium (Ca2+) signaling plays a pivotal role in controlling various cellular processes such as secretion, differentiation, proliferation, motility, and cell death through the release of Ca2+ from internal stores and entry from extracellular fluid. In bone, receptor activator of NF-kB ligand (RANKL) evokes intracellular Ca2+ oscillations, which trigger nuclear factor-activated T cells cytoplasmic 1 (NFAT2 or NFATc1) -responsive gene transcription and drives osteoclast (OC) differentiation. However, what protein(s) are involved in regulating Ca2+ oscillations during OC differentiation and function remain largely unidentified. Although our in vitro study demonstrated that regulator of G-protein signaling (Rgs) 12 plays crucial roles in Ca2+ oscillations and OC differentiation, how Rgs12 contributes to calcium signaling, OC differentiation and bone diseases has not been defined. We created a mouse model in which Rgs12 was specifically deleted in OC precursors in developmental and postnatal stages by crossing Rgs12 conditional knockout mice with CD11b-Cre and inducible Mx1-Cre transgenic mice. Rgs12-deficient mice displayed the phenotype of increased bone mass and decreased OC numbers. Deletion of Rgs12 blocked OC marker gene expression, and impaired OC differentiation and function, which were associated with decreased expression of NFAT2 and impaired Ca2+ oscillations. Ectopic expression of constitutive active NFAT2 (ca-NFAT2) in Rgs12-deficient OC precursor cells restored defective OC differentiation and function. To determine if bone resorption and turnover can be stimulated in the absence of Rgs12, Rgs12-deficient mice were subjected to ovariectomy and lipodysaccharide(LPS)-induction for bone loss in calvarial and alveolar bone. Specific deletion of Rgs12 in the OC precursor cells significantly inhibited pathologic osteoclastogenesis and bone destruction. Thus, our study demonstrates that Rgs12 is a key regulator of osteoclastogenesis through modulating the RANKL-Rgs12-Ca2+ oscillations-NFAT2 pathway and identifies Rgs12 as a potential therapeutic target for osteoporosis and inflammation-caused bone loss. Keywords: osteoclast, Rgs12, calcium oscillations, NFAT2