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.
Highlights
Bone destruction is a major cause of disability associated with many skeletal diseases, such as rheumatoid arthritis (RA), psoriatic arthritis, periodontitis and peri-prosthetic loosening[1,2,3,4,5]
We found that Gα13 is a RANKL-inducible G-protein that is highly expressed in multinucleated osteoclasts and plays an important feedback inhibitory role in controlling osteoclast actin ring formation and resorptive function
We observed that low Gα13 expression levels were maintained throughout the early stage of differentiation and were not highly induced until three days after RANKL stimulation, when the cells generally started fusion and became mature multinucleated giant osteoclasts in cultures (Fig. 1A,B)
Summary
Bone destruction is a major cause of disability associated with many skeletal diseases, such as rheumatoid arthritis (RA), psoriatic arthritis, periodontitis and peri-prosthetic loosening[1,2,3,4,5]. The unique osteoclastic actin ring structure makes the sealing zone an isolated resorptive microenvironment that concentrates the secreted protons and degrading enzymes for efficient resorption to occur[12,13,14] Upon stimulation, such as attachment to integrins and/or cytokine activation by M-CSF or RANKL, osteoclasts undergo rapid cytoskeletal reorganization, appear polarized and form actin rings (the actin rings display as actin rings/belts in in vitro cultures). We found that Gα13 is a RANKL-inducible G-protein that is highly expressed in multinucleated osteoclasts and plays an important feedback inhibitory role in controlling osteoclast actin ring formation and resorptive function. We found that Gα13 deficiency in myeloid lineage does not affect early stages of osteoclast differentiation, but enhances gene expression responsible for osteoclast fusion, resorption and cytoskeletal reorganization. We found that Gα13 expression is inversely correlated with TNF and RA disease activity, suggesting that appropriate modulation of Gα13 would provide an alternative strategy to control osteoclast function thereby preventing bone loss
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