Dataset Information

The phosphoinositide 3-kinase isoform PI3K? regulates osteoclast-mediated bone resorption in humans and mice.

ABSTRACT:

Objective

While 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 PI3K? 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 PI3K? in osteoclast development and function using a combined genetic and pharmacologic approach.

Methods

The role of PI3K? in primary human and murine osteoclast cultures was tested with the PI3K?-selective inhibitor TGX221 and by using PI3K?(-/-) mice. The trabecular bone architecture of PI3K?(-/-) mice was evaluated using micro-computed tomography and histomorphometric analyses.

Results

The expression of PI3K? 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 PI3K? inhibitor TGX221 or by the genetic deficiency of PI3K?. This was likely due to defective cytoskeletal reorganization and vesicular trafficking, since PI3K?(-/-) 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. PI3K?(-/-) mice had significantly increased trabecular bone volume and showed abnormal osteoclast morphology with defective resorption pit formation.

Conclusion

PI3K? plays an important role in osteoclast development and function and is required for in vivo bone homeostasis.

SUBMITTER: Gyori D

PROVIDER: S-EPMC4314683 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Publications

The phosphoinositide 3-kinase isoform PI3Kβ regulates osteoclast-mediated bone resorption in humans and mice.

Győri Dávid D Csete Dániel D Benkő Szilvia S Kulkarni Suhasini S Mandl Péter P Dobó-Nagy Csaba C Vanhaesebroeck Bart B Stephens Len L Hawkins Phillip T PT Mócsai Attila A

Arthritis & rheumatology (Hoboken, N.J.) 20140801 8

<h4>Objective</h4>While 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 osteocla ...[more]

PMID: 24719382

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