G-protein Gα13 functions as a cytoskeletal and mitochondrial regulator to restrain osteoclast function View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-12

AUTHORS

Shinichi Nakano, Kazuki Inoue, Cheng Xu, Zhonghao Deng, Viktoriya Syrovatkina, Gregory Vitone, Liang Zhao, Xin-Yun Huang, Baohong Zhao

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. More... »

PAGES

4236

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-40974-z

DOI

http://dx.doi.org/10.1038/s41598-019-40974-z

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30862896


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73 disease activity
74 early differentiation
75 elevated bone resorptive capacity
76 erosion
77 excessive bone resorption
78 expression
79 expression levels
80 function
81 functional control
82 fusion
83 gene expression
84 genes
85 genome wide analysis
86 genome wide regulation
87 giant osteoclasts
88 homeostasis
89 inflammatory arthritis
90 inhibition
91 levels
92 lineages
93 loosening
94 loss
95 maintenance
96 mechanism
97 mice
98 mitochondrial biogenesis
99 mitochondrial regulators
100 morphology
101 myeloid osteoclast lineage
102 normal bone remodeling
103 osteoclast adhesion
104 osteoclast function
105 osteoclast lineage
106 osteoclast resorptive function
107 osteoclastic bone erosion
108 osteoclasts
109 osteoporotic bone phenotype
110 pathway
111 patients
112 peri-prosthetic loosening
113 periodontitis
114 phenotype
115 protein Gα13
116 protein Gα13 functions
117 psoriatic arthritis
118 regulation
119 regulator
120 related gene expression
121 related genes
122 remodeling
123 resorption
124 resorptive capacity
125 resorptive function
126 rheumatoid arthritis
127 role
128 significant correlation
129 skeletal disease
130 study
131 target
132 therapeutic target
133 wide analysis
134 wide regulation
135 ΔM mice
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