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Sci Rep. 2019 Mar 12;9(1):4236. doi: 10.1038/s41598-019-40974-z.

G-protein Gα13 functions as a cytoskeletal and mitochondrial regulator to restrain osteoclast function.

Author information

1
Arthritis and Tissue Degeneration Program and The David Z, Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA.
2
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
3
Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
4
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, USA.
5
Arthritis and Tissue Degeneration Program and The David Z, Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA. zhaob@hss.edu.
6
Department of Medicine, Weill Cornell Medical College, New York, New York, USA. zhaob@hss.edu.
7
Graduate Program in Cell & Developmental Biology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA. zhaob@hss.edu.

Abstract

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 Gα13 in inhibition of osteoclast adhesion, fusion and bone resorptive function. Gα13 is highly expressed in mature multinucleated osteoclasts, but not during early differentiation. Deficiency of Gα13 in myeloid osteoclast lineage (Gα13ΔM/ΔM mice) leads to super spread morphology of multinucleated giant osteoclasts with elevated bone resorptive capacity, corroborated with an osteoporotic bone phenotype in the Gα13ΔM/ΔM mice. Mechanistically, Gα13 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 Gα13, identifying Gα13 as a critical cytoskeletal regulator in osteoclasts. We also identify a genome wide regulation of genes responsible for mitochondrial biogenesis and function by Gα13 in osteoclasts. Furthermore, the significant correlation between Gα13 expression levels, TNF activity and RA disease activity in RA patients suggests that the Gα13 mediated mechanisms represent attractive therapeutic targets for diseases associated with excessive bone resorption.

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