Role of regulator of G protein signaling proteins in bone

Abstract

Regulators of G protein signaling (RGS) proteins are a family with more than 30 proteins that all contain an RGS domain. In the past decade, increasing evidence has indicated that RGS proteins play crucial roles in the regulation of G protein coupling receptors (GPCR), G proteins, and calcium signaling during cell proliferation, migration, and differentiation in a variety of tissues. In bone, those proteins modulate bone development and remodeling by influencing various signaling pathways such as GPCR-G protein signaling, Wnt, calcium oscillations and PTH. This review summarizes the recent advances in the understanding of the regulation of RGS gene expression, as well as the functions and mechanisms of RGS proteins, especially in regulating GPCR-G protein signaling, Wnt signaling, calcium oscillations signaling and PTH signaling during bone development and remodeling. This review also highlights the regulation of different RGS proteins in osteoblasts, chondrocytes and osteoclasts. The knowledge from the recent advances of RGS study summarized in the review would provide the insights into new therapies for bone diseases.

Figure 1

RGS proteins in the regulation of GPCR, PTH, and Wnt signaling pathways during bone remodeling. Binding of Wnt to the FZD receptor induces β-catenin accumulation, which translocates to the nucleus to activate target gene transcription, which is important for osteoblast differentiation. Axin2, a member of the RGS family, is found to form a stable complex with β-catenin to prevent its activation without Wnt. In osteoblasts, binding of PTH to its G-protein-coupled receptor (PTHR/PTHrPR) induces the expression of RGS proteins such as RGS2 and RGS5 via activation of the cAMP/PKA- pathway. RGS2 predominately binds to the Gq-subunit of the G-protein complex and inhibits activation of the PKC/Ca²⁺ dependent signaling cascade, which is involved in osteoblast differentiation. RGS5 likely regulates osteoblast differentiation through the regulation of PTH levels. In osteoclasts, PKC/Ca²⁺-induced NFATc1 is crucial for osteoclast differentiation. PLC is suggested to regulate the NFATc1 expression through IP3/DAG. RGS10 and RGS12 regulate the activity of Gαq and Gαi/o to activate PLC, which is critical for calcium oscillation and the activation of NFATc1. NFATc1 activation leads to osteoclast differentiation. RGS18 negatively regulates osteoclast differentiation through acidosis-induced osteoclastogenic OGR1/NFAT signaling pathway.