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A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction.

ABSTRACT: Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are required for loading-induced Sost suppression and bone formation. FFSS signaling drives class IIa HDAC nuclear translocation through a signaling pathway involving direct HDAC5 tyrosine 642 phosphorylation by focal adhesion kinase (FAK), a HDAC5 post-translational modification that controls its subcellular localization. Osteocyte cell adhesion supports FAK tyrosine phosphorylation, and FFSS triggers FAK dephosphorylation. Pharmacologic FAK catalytic inhibition reduces Sost mRNA expression in vitro and in vivo. These studies demonstrate a role for HDAC5 as a transducer of matrix-derived cues to regulate cell type-specific gene expression.

SUBMITTER: Sato T

PROVIDER: S-EPMC7329900 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction.

Sato Tadatoshi T Verma Shiv S Andrade Christian D Castro CDC Omeara Maureen M Campbell Nia N Wang Jialiang S JS Cetinbas Murat M Lang Audrey A Ausk Brandon J BJ Brooks Daniel J DJ Sadreyev Ruslan I RI Kronenberg Henry M HM Lagares David D Uda Yuhei Y Pajevic Paola Divieti PD Bouxsein Mary L ML Gross Ted S TS Wein Marc N MN

Nature communications 20200701 1

Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are requi ...[more]

PMID: 32612176

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Project description:BackgroundThe key focal adhesion protein β1 integrin plays an essential role in early skeletal development. However, roles of β1 integrin expression in osteocytes during the regulation of bone homeostasis and mechanotransduction are incompletely understood.Materials and methodsTo study the in vivo function of osteocyte β1 integrin in bone, we utilized the 10-kb Dmp1 (Dentin matrix acidic phosphoprotein 1)-Cre to generate mice with β1 integrin deletion in this cell type. Micro-computerized tomography, bone histomorphometry and immunohistochemistry were performed to determine the effects of osteocyte β1 integrin loss on bone mass accrual and biomechanical properties. In vivo tibial loading model was applied to study the possible involvement of osteocyte β1 integrin in bone mechanotransduction.ResultsLoss of β1 integrin expression in osteocytes resulted in a severe low bone mass and impaired biomechanical properties in load-bearing long bones and spines, but not in non-weight-bearing calvariae, in mice. The loss of β1 integrin led to enlarged size of lacunar-canalicular system, abnormal cell morphology, and disorientated nuclei in osteocytes. Furthermore, β1 integrin loss caused shortening and disorientated collagen I fibers in long bones. Osteocyte β1 integrin loss did not impact the osteoclast activities, but significantly reduced the osteoblast bone formation rate and, in the meantime, enhanced the adipogenic differentiation of the bone marrow stromal cells in the bone microenvironment. In addition, tibial loading failed to accelerate the anabolic bone formation and improve collagen I fiber integrity in mutant mice.ConclusionsOur studies demonstrate an essential role of osteocyte β1 integrin in regulating bone homeostasis and mechanotransduction. The transnational potential of this article : This study reveals the regulatory roles of osteocyte β1 integrin in vivo for the maintenance of bone mass accrual, biomechanical properties, extracellular matrix integrity as well as bone mechanobiology, which defines β1 integrin a potential therapeutic target for skeletal diseases, such as osteoporosis.

Dataset Information

A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction.

Publications

A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction.

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