[Frontiers in Bioscience 15, 957-985, June 1, 2010]
G Protein and Its signaling pathway in bone development and disease

Mengrui Wu1,2, Lianfu Deng2, Guochun Zhu2, Yi-Ping Li1,2,3,4

1Life Science College, Zhejiang University, 388 Yuhang Road, Hongzhou 310058, People's Republic of China, 2Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, School of Medicine, Jiao Tong University, 197 Ruijin er Road, Shanghai 200025, People's Republic of China, 3Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston, Massachusetts 02115, USA, 4Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, Massachusetts 02115, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. G proteins in bone
3.1. Gs/GNAS signaling
3.1.1. Human disease
3.1.2. Mouse model
3.1.3. Signaling pathway and molecular mechanism
3.2. Gq/11 signaling
3.2.1. Gq/11 and osteoblast proliferation
3.2.2. Gq/11 and osteoblast differentiation
3.3. Gi signaling
3.3.1. Gi and osteoblastogenesis
3.3.2. Gi is coupled to receptor sensing non-biomolecular stimuli
3.4. G12/13 signaling
3.5. G proteins in osteoclasts
4. G protein coupled receptors and ligands in bone
4.1. PTH/PTHrP and PTH1R in bone
4.1.1. Physiological role of PTH/PTHrP in bone
4.1.1.1. Calcium homeostasis
4.1.1.2. Anabolic and catabolic regulator of bone formation
4.1.2. Signaling pathway and molecular effectors regulated by PTH/PTHrP in osteoblasts
4.2. Calcium sensing receptor (CaSR/CaR)
4.3. Calcitonin
4.3.1. Calcitonin and the calcitonin receptor
4.3.2. Other calcitonin family peptides and their receptors
4.4. Cannabinoid receptor
4.5. RXFP/relaxin family peptide
4.6. Non-canonical Wnt-G protein signaling in bone
4.7. Proton sensing OGR1/ovarian cancer G-protein coupled receptor (GPR68)
4.8. G protein-coupled receptor 30/G protein-coupled estrogen receptor: GPCR for estrogen
5.Regulating G protein signaling in bone
5.1. RGS/regulator of G protein signaling
5.2. GRK-beta-arrestin system
5.3. NHERF
6. Drug development based on G protein signaling
7. Summary and Perspectives
8. Acknowledgments
9. References

1. ABSTRACT

G protein signaling is comprised of G protein coupled receptors (GPCRs) that detect ligands or sense cations, heterotrimeric G proteins, and downstream effectors and regulators. G protein signaling plays important roles in bone development, remodeling, and disease. In human cases, mutations of certain GPCRs and G proteins impair bone development and metabolism, resulting in bone diseases. This review focuses on the functions of G proteins and GPCRs in osteoblasts and osteoclasts, their signaling pathways, and their gene mutations in mouse models and human diseases. We have discussed the roles of all four types of G proteins (i.e. Gs, Gq/11, Gi/o, and G12/13) and assessed the roles of the GPCRs, such as type 1 Parathyroid hormone receptor (PTH1R), calcitonin receptor, cation sensing receptor (CaSR), relaxin family peptides, cannabinoid receptor, frizzleds, and proton sensing receptor in normal bone formation and remodeling. The roles of regulators of G protein signaling (RGS) and GTPase-activating proteins (GAP) in G-protein signaling pathways are also reviewed. Lastly, we give perspective for the research of G protein signaling in bone development and disease.