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Substrate stiffness regulates the differentiation profile and functions of osteoclasts via cytoskeletal arrangement.
- Source :
-
Cell proliferation [Cell Prolif] 2022 Jan; Vol. 55 (1), pp. e13172. Date of Electronic Publication: 2021 Dec 24. - Publication Year :
- 2022
-
Abstract
- Objectives: Aging and common diseases alter the stiffness of bone tissue, causing changes to the microenvironment of the mechanosensitive bone cells. Osteoclasts, the sole bone-resorbing cells, play a vital role in bone remodeling. This study was performed to elucidate the mechanism through which osteoclasts sense and react to substrate stiffness signals.<br />Materials and Methods: We fabricated polydimethylsiloxane (PDMS) substrates of different stiffness degrees for osteoclast formation progressed from osteoclast precursors including bone marrow-derived macrophages (BMMs) and RAW264.7 monocytes. Osteoclast differentiation in response to the stiffness signals was determined by examining the cell morphology, fusion/fission activities, transcriptional profile, and resorption function. Cytoskeletal changes and mechanosensitive adhesion molecules were also assessed.<br />Results: Stiffer PDMS substrates accelerated osteoclast differentiation, firstly observed by variations in their morphology and fusion/fission activities. Upregulation of canonical osteoclast markers (Nfatc1, Acp5, Ctsk, Camk2a, Mmp9, Rela, and Traf6) and the fusion master regulator DC-stamp were detected on stiffer substrates, with similar increases in their bone resorption functions. Additionally, the activation of cytoskeleton-associated adhesion molecules, including fibronectin and integrin αvβ3, followed by biochemical signaling cascades of paxillin, FAK, PKC, and RhoA, was detected on the stiffer substrates.<br />Conclusions: This is the first study to provide evidence proving that extracellular substrate stiffness is a strong determinant of osteoclast differentiation and functions. Higher stiffness upregulated the differentiation profile and activity of osteoclasts, revealing the mechanical regulation of osteoclast activity in bone homeostasis and diseases.<br /> (© 2021 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)
- Subjects :
- Animals
Biomarkers metabolism
Bone Resorption genetics
Bone Resorption pathology
Cell Fusion
Cell Shape drug effects
Cytoskeleton drug effects
Elasticity
Extracellular Matrix drug effects
Extracellular Matrix metabolism
Fibronectins metabolism
Gene Expression Profiling
Gene Expression Regulation drug effects
Integrins metabolism
Mice
Models, Biological
Osteoclasts drug effects
Osteoclasts metabolism
RAW 264.7 Cells
Signal Transduction drug effects
Substrate Specificity
Cell Differentiation drug effects
Cytoskeleton metabolism
Dimethylpolysiloxanes pharmacology
Osteoclasts cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2184
- Volume :
- 55
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell proliferation
- Publication Type :
- Academic Journal
- Accession number :
- 34953003
- Full Text :
- https://doi.org/10.1111/cpr.13172