A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

Sato, Tadatoshi; Verma, Shiv Kumar; Andrade, Christian D. Castro; O'Meara, Maureen J; Campbell, Nia; Wang, Jialiang S.; Çetinbaş, Murat; Lang, Audrey; Ausk, Brandon J.; Brooks, Daniel J.; Sadreyev, Ruslan I.; Kronenberg, Henry M.; Lagares, David; Uda, Yutaka; Pajevic, Paola Divieti; Bouxsein, Mary L.; Gross, Ted S.; Wein, Marc N.

doi:10.1038/s41467-020-17099-3

Cited by 66 publications

(60 citation statements)

References 104 publications

(118 reference statements)

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“…The importance for Kindlin-2 in osteocyte mechanotransduction could be related to its functions in FA. Previous studies showed that FA proteins are essential for bone mass maintenance in mechanical stimulation, such as integrin-β1 81 – 83 , FAK 84 , and Pinch1/2 85 , 86 . Our results demonstrate that Kindlin-2 controls osteocyte FA formation, cell spreading, cell attachment, and cell morphology both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

Qin

et al. 2021

Commun Biol

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Osteocytes act as mechanosensors in bone; however, the underlying mechanism remains poorly understood. Here we report that deleting Kindlin-2 in osteocytes causes severe osteopenia and mechanical property defects in weight-bearing long bones, but not in non-weight-bearing calvariae. Kindlin-2 loss in osteocytes impairs skeletal responses to mechanical stimulation in long bones. Control and cKO mice display similar bone loss induced by unloading. However, unlike control mice, cKO mice fail to restore lost bone after reloading. Osteocyte Kindlin-2 deletion impairs focal adhesion (FA) formation, cytoskeleton organization and cell orientation in vitro and in bone. Fluid shear stress dose-dependently increases Kindlin-2 expression and decreases that of Sclerostin by downregulating Smad2/3 in osteocytes; this latter response is abolished by Kindlin-2 ablation. Kindlin-2-deficient osteocytes express abundant Sclerostin, contributing to bone loss in cKO mice. Collectively, we demonstrate an indispensable novel role of Kindlin-2 in maintaining skeletal responses to mechanical stimulation by inhibiting Sclerostin expression during osteocyte mechanotransduction.

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Section: Discussionmentioning

confidence: 99%

Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

Qin

et al. 2021

Commun Biol

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“…Immunoblotting and ELISA Immunoblotting was performed as previously described [69,70]. For both Ocy454 and MC3T3-E1 Sp7 knockdown and overexpressing cells, whole cell lysates were prepared using TNT (Tris-NaCl-Tween buffer, 20 mM Tris-HCl pH = 8, mM NaCl, 0.5% Triton X-100 containing protease inhibitor (PI), 1 mM NaF, 1 mM DTT, 1 mM vanadate).…”

Section: Ocy454mentioning

confidence: 99%

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Wang

Kamath

Mirzamohammadi

et al. 2021

Preprint

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Osteocytes use an elaborate network of dendritic connections to control bone remodeling. Some osteoblasts embed within mineralized bone matrix, change shape, and become osteocytes. The molecular circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites. Unbiased profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues phenotypic and molecular defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates overt defects in osteocyte maturation in vivo in the absence of Sp7. Sp7-dependent gene networks enriched in developing osteocytes are associated with rare and common human skeletal traits. Moreover, humans homozygous for the osteogenesis imperfecta-causing SP7R316C mutation show dramatic defects in osteocyte morphology. Genes that mark osteocytes in vivo and that are regulated by Sp7 in vitro are highly enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. Taken together, these findings reveal a crucial role for Sp7 and its target gene Osteocrin in osteocytogenesis, demonstrating that pathways that control osteocyte development influence human bone diseases.

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“…These data do not preclude a transcriptional control of the Sost gene by osteoanabolic stimuli ( Tu et al, 2012 ; Sato et al, 2020 ). Rather, they add an important downstream check point for regulating sclerostin protein bioavailability with remarkable temporal control.…”

Section: Discussionmentioning

confidence: 70%

“…Finally, we link sclerostin degradation not only to skeletal physiology in mice but also to human disease using Gaucher disease iPSCs. These data do not preclude a transcriptional control of the Sost gene by osteoanabolic stimuli (47,48). Rather, they add an important downstream check point for regulating sclerostin protein bioavailability with remarkable temporal control.…”

Section: Discussionmentioning

confidence: 85%

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

Gould

Williams

Joca

et al. 2021

eLife

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The down regulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minutes-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically- and hormonally-activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

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A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

Cited by 66 publications

References 104 publications

Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

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