G-protein Gα(13) functions as a cytoskeletal and mitochondrial regulator to restrain osteoclast function

Excessive osteoclastic bone erosion disrupts normal bone remodeling and leads to bone loss in many skeletal diseases, including inflammatory arthritis, such as rheumatoid arthritis (RA) and psoriatic arthritis, periodontitis and peri-prosthetic loosening. Functional control of osteoclasts is critical for the maintenance of bone homeostasis. However, the mechanisms that restrain osteoclast resorptive function are not fully understood. In this study, we identify a previously unrecognized role for G-protein Gα(13) in inhibition of osteoclast adhesion, fusion and bone resorptive function. Gα(13) is highly expressed in mature multinucleated osteoclasts, but not during early differentiation. Deficiency of Gα(13) in myeloid osteoclast lineage (Gα(13)(ΔM/ΔM) mice) leads to super spread morphology of multinucleated giant osteoclasts with elevated bone resorptive capacity, corroborated with an osteoporotic bone phenotype in the Gα(13)(ΔM/ΔM) mice. Mechanistically, Gα(13) functions as a brake that restrains the c-Src, Pyk2, RhoA-Rock2 mediated signaling pathways and related gene expressions to control the ability of osteoclasts in fusion, adhesion, actin cytoskeletal remodeling and resorption. Genome wide analysis reveals cytoskeleton related genes that are suppressed by Gα(13), identifying Gα(13) as a critical cytoskeletal regulator in osteoclasts. We also identify a genome wide regulation of genes responsible for mitochondrial biogenesis and function by Gα(13) in osteoclasts. Furthermore, the significant correlation between Gα(13) expression levels, TNF activity and RA disease activity in RA patients suggests that the Gα(13) mediated mechanisms represent attractive therapeutic targets for diseases associated with excessive bone resorption.