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. Bone homeostasis is tightly regulated by the balance between osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. 1 Pathological conditions such as osteoporosis, inflammation, and cancer break this balance in favor of the augmentation of OC activity, resulting in net bone loss. 2-4 As a result, patients with these diseases suffer from pain and risk of bone fracture. Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs. 13 Robust induction of NFAT2 is dependent on calcium (Ca 2+ ) oscillations. 14 Ca 2+ oscillations lead to calcineurin-mediated activation of NFAT2 and ensure NFAT2 long-lasting transcriptional activation. 13,14 Despite these...

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