Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa, Masahiro; Nakamura, Masaki; Masuda, Hironari; Hirose, Jun; Kadono, Yuho; Iwasawa, Masaki; Nagase, Yuichi; Ueki, Kohjiro; Kadowaki, Takashi; Sasaki, Takehiko; Kato, Shigeaki; Nakamura, Hiroaki; Tanaka, Sakae; Takayanagi, Hiroshi

doi:10.1002/jbmr.1703

Cited by 35 publications

(31 citation statements)

References 60 publications

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“…In contrast, no substantial changes were seen in parallel macrophage cultures (Figure 1B). Therefore, consistent with a recent report (31), PI3Kβ was dramatically and specifically up-regulated during osteoclast development.…”

Section: Resultssupporting

confidence: 93%

The Phosphoinositide 3‐Kinase Isoform PI3Kβ Regulates Osteoclast‐Mediated Bone Resorption in Humans and Mice

Győri

Csete

Benkő

et al. 2014

Arthritis & Rheumatology

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ObjectiveWhile phosphoinositide 3-kinases (PI3Ks) are involved in various intracellular signal transduction processes, the specific functions of the different PI3K isoforms are poorly understood. We have previously shown that the PI3Kβ isoform is required for arthritis development in the K/BxN serum–transfer model. Since osteoclasts play a critical role in pathologic bone loss during inflammatory arthritis and other diseases, we undertook this study to test the role of PI3Kβ in osteoclast development and function using a combined genetic and pharmacologic approach.MethodsThe role of PI3Kβ in primary human and murine osteoclast cultures was tested with the PI3Kβ-selective inhibitor TGX221 and by using PI3Kβ−/− mice. The trabecular bone architecture of PI3Kβ−/− mice was evaluated using micro–computed tomography and histomorphometric analyses.ResultsThe expression of PI3Kβ was strongly and specifically up-regulated during in vitro osteoclast differentiation. In vitro development of large multinucleated osteoclasts from human or murine progenitors and their resorption capacity were strongly reduced by the PI3Kβ inhibitor TGX221 or by the genetic deficiency of PI3Kβ. This was likely due to defective cytoskeletal reorganization and vesicular trafficking, since PI3Kβ−/− mouse multinucleated cells failed to form actin rings and retained intracellular acidic vesicles and cathepsin K. In contrast, osteoclast-specific gene expression and the survival and apoptosis of osteoclasts were not affected. PI3Kβ−/− mice had significantly increased trabecular bone volume and showed abnormal osteoclast morphology with defective resorption pit formation.ConclusionPI3Kβ plays an important role in osteoclast development and function and is required for in vivo bone homeostasis.

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Section: Resultssupporting

confidence: 93%

The Phosphoinositide 3‐Kinase Isoform PI3Kβ Regulates Osteoclast‐Mediated Bone Resorption in Humans and Mice

Győri

Csete

Benkő

et al. 2014

Arthritis & Rheumatology

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“…8). The critical role of PI3K-Akt activity in osteoclast differentiation and activation is well-documented202126272829. Although several endogenous factors that oppose osteoclast differentiation were described, most are downregulated under osteoclastogenic condition.…”

Section: Discussionmentioning

confidence: 99%

Gα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway

et al. 2017

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Many positive signalling pathways of osteoclastogenesis have been characterized, but negative signalling pathways are less well studied. Here we show by microarray and RNAi that guanine nucleotide-binding protein subunit α13 (Gα13) is a negative regulator of osteoclastogenesis. Osteoclast-lineage-specific Gna13 conditional knockout mice have a severe osteoporosis phenotype. Gna13-deficiency triggers a drastic increase in both osteoclast number and activity (hyper-activation), mechanistically through decreased RhoA activity and enhanced Akt/GSK3β/NFATc1 signalling. Consistently, Akt inhibition or RhoA activation rescues hyper-activation of Gna13-deficient osteoclasts, and RhoA inhibition mimics the osteoclast hyperactivation resulting from Gna13-deficiency. Notably, Gα13 gain-of-function inhibits Akt activation and osteoclastogenesis, and protects mice from pathological bone loss in disease models. Collectively, we reveal that Gα13 is a master endogenous negative switch for osteoclastogenesis through regulation of the RhoA/Akt/GSK3β/NFATc1 signalling pathway, and that manipulating Gα13 activity might be a therapeutic strategy for bone diseases.

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“…Calvarial bones of the mice injected with adenovirus expressing LacZ or coronin 1A were analysed using ScanXmate-A100S Scanner (ComScanTechno, Yokohama, Japan) as described previously62. Three-dimensional microstructure images were reconstituted and the void volume on the surface of the calvarial bones was calculated by TRI/3D-BON software (RATOC System Engineering, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Actin-binding protein coronin 1A controls osteoclastic bone resorption by regulating lysosomal secretion of cathepsin K

Ohmae

Noma

Toyomoto

et al. 2017

Sci Rep

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Osteoclasts degrade bone matrix proteins via the secretion of lysosomal enzymes. However, the precise mechanisms by which lysosomal components are transported and fused to the bone-apposed plasma membrane, termed ruffled border membrane, remain elusive. Here, we identified coronin 1A as a negative regulator of exocytotic release of cathepsin K, one of the most important bone-degrading enzymes in osteoclasts. The modulation of coronin 1A expression did not alter osteoclast differentiation and extracellular acidification, but strongly affected the secretion of cathepsin K and osteoclast bone-resorption activity, suggesting the coronin 1A-mediated regulation of lysosomal trafficking and protease exocytosis. Further analyses suggested that coronin 1A prevented the lipidation-mediated sorting of the autophagy-related protein LC3 to the ruffled border and attenuated lysosome–plasma membrane fusion. In this process, the interactions between coronin 1A and actin were crucial. Collectively, our findings indicate that coronin 1A is a pivotal component that regulates lysosomal fusion and the secretion pathway in osteoclast-lineage cells and may provide a novel therapeutic target for bone diseases.

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Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Cited by 35 publications

References 60 publications

The Phosphoinositide 3‐Kinase Isoform PI3Kβ Regulates Osteoclast‐Mediated Bone Resorption in Humans and Mice

The Phosphoinositide 3‐Kinase Isoform PI3Kβ Regulates Osteoclast‐Mediated Bone Resorption in Humans and Mice

Gα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway

Actin-binding protein coronin 1A controls osteoclastic bone resorption by regulating lysosomal secretion of cathepsin K

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