Microfluidics approach to investigate the role of dynamic similitude in osteocyte mechanobiology

Middleton, Kevin; Kondiboyina, Avinash; Borrett, Michael; Cui, Yi; X, Mei; You, Lidan

doi:10.1002/jor.23773

Cited by 9 publications

(7 citation statements)

References 45 publications

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“…The cells were stained with Fura‐2 AM (Thermo Fisher Scientific, MA) for 45 min before imaging. Using a custom syringe pump, the cells were stimulated with OFF at 4 Pa peak shear stress and 1 Hz frequency for up to 4 min. Static control cells were seeded into ibidi channels without applying OFF.…”

Section: Methodsmentioning

confidence: 99%

OCY454 Osteocytes as an in Vitro Cell Model for Bone Remodeling Under Mechanical Loading

Shao

Vivian

et al. 2019

Journal Orthopaedic Research

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Osteocytes' mechano-regulation of bone formation and resorption is key to maintaining appropriate bone health. Although extensive in vitro studies have explored osteocyte mechanobiology using the well-established MLO-Y4 cell model, the low amount of sclerostin secreted by this cell line renders it inadequate for studying cross-talk between osteocytes and osteoblasts under mechanical loading. Here, we investigated the potential of the sclerostin-expressing OCY454 osteocyte cell model in fulfilling this role. Fully differentiated OCY454 cells were tested for mechano-sensitivity by measuring changes in protein secretion, total adenosine triphosphate (ATP) content, and intracellular calcium in response to oscillatory fluid flow. Increases in sclerostin expression and total ATP content were observed. However, very low levels of receptor activator of the nuclear factor κ-B ligand were detected, and there was a great inconsistency in calcium response. Conditioned medium (CM) from OCY454 cells was then used to culture osteoblast and osteoclast precursors. Osteoblast activity was quantified with alkaline phosphatase (ALP) and Alizarin Red S stain, while osteoclast differentiation was quantified with tartrate-resistant acid phosphatase (TRAP) staining. We demonstrated that mechanically stimulated OCY454 cells released soluble factors that increased osteoblasts' ALP activity (p < 0.05) and calcium deposition (p < 0.05). There was also a significant decrease of large-sized TRAP-positive osteoclasts when osteoclast precursors were treated with CM from flow-stimulated OCY454 cells (p < 0.05). Results from this study suggest that OCY454 cells respond to mechanical loading with the release of key factors such as sclerostin to regulate downstream bone cells, thus demonstrating its potential as a novel cell model for in vitro osteocyte mechanobiology studies.

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Section: Methodsmentioning

confidence: 99%

OCY454 Osteocytes as an in Vitro Cell Model for Bone Remodeling Under Mechanical Loading

Shao

Vivian

et al. 2019

Journal Orthopaedic Research

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“…Calcium ions play a very important role in osteocyte mechanotransduction. Application of mechanical load initiates rapid response of intracellular calcium ions influx [ 46 , 58 , 59 ]. These ions act as signals to be delivered to neighbouring cells through ion channels.…”

Section: Resultsmentioning

confidence: 99%

The role of osteocytes-specific molecular mechanism in regulation of mechanotransduction – A systematic review

Chow

Wong

et al. 2021

Journal of Orthopaedic Translation

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Background Osteocytes, composing over 90% of bone cells, are well known for their mechanosensing abilities. Aged osteocytes with impaired morphology and function are less efficient in mechanotransduction which will disrupt bone turnover leading to osteoporosis. The aim of this systematic review is to delineate the mechanotransduction mechanism at different stages in order to explore potential target for therapeutic drugs. Methods A systematic literature search was performed in PubMed and Web of Science. Original animal, cell and clinical studies with available English full-text were included. Information was extracted from the included studies for review. Results The 26 studies included in this review provided evidence that mechanical loading are sensed by osteocytes via various sensing proteins and transduced to different signaling molecules which later initiate various biochemical responses. Studies have shown that osteocyte plasma membrane and cytoskeletons are emerging key players in initiating mechanotransduction. Bone regulating genes expressions are altered in response to load sensed by osteocytes, but the genes involved different signaling pathways and the spatiotemporal expression pattern had made mechanotransduction mechanism complicated. Most of the included studies described the important role of osteocytes in pathways that regulate mechanosensing and bone remodeling. Conclusions This systematic review provides an up-to-date insight to different steps of mechanotransduction. A better understanding of the mechanotransduction mechanism is beneficial in search of new potential treatment for osteoporotic patients. By delineating the unique morphology of osteocytes and their interconnected signaling network new targets can be discovered for drug development. Translational potential of this article This systematic review provides an up-to-date sequential overview and highlights the different osteocyte-related pathways and signaling molecules during mechanotransduction. This allows a better understanding of mechanotransduction for future development of new therapeutic interventions to treat patients with impaired mechanosensitivity.

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“…[ 72 ] Furthermore, fluid flow in two dimensional in vitro studies has a Reynolds number orders of magnitude larger than what can be expected in vivo. [ 73 ] In vitro experiments under parallel‐plate fluid flow conditions thus may prove that osteocytes are mechanosensitive, but the fluid flow conditions are inherently incomparable to what may occur within the LCN in vivo.…”

Section: Discussionmentioning

confidence: 99%

Closing the osteon: Do osteocytes sense strain rate rather than fluid flow?

Smit

2021

BioEssays

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Osteons are cylindrical structures of bone created by matrix resorbing osteoclasts, followed by osteoblasts that deposit new bone. Osteons align with the principal loading direction and it is thought that the osteoclasts are directed by osteocytes, the mechanosensitive cells that reside inside the bone matrix. These osteocytes are presumably controlled by interstitial fluid flow, induced by the physiological loading of bones. Here I consider the stimulation of osteocytes while the osteon is closed by osteoblasts. In a conceptual finite element model, bone is considered a poro-elastic material and subjected to locomotion-induced loading conditions. It appears that the magnitude of flow is constant along the closing cone, while shear strain rate in the bone matrix diminishes linearly with the deposition of bone. This suggests that shear strain rate, rather than fluid flow, is the physical cue that controls osteocytes and bone deposition in newly formed osteons.

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Microfluidics approach to investigate the role of dynamic similitude in osteocyte mechanobiology

Cited by 9 publications

References 45 publications

OCY454 Osteocytes as an in Vitro Cell Model for Bone Remodeling Under Mechanical Loading

OCY454 Osteocytes as an in Vitro Cell Model for Bone Remodeling Under Mechanical Loading

The role of osteocytes-specific molecular mechanism in regulation of mechanotransduction – A systematic review

Closing the osteon: Do osteocytes sense strain rate rather than fluid flow?

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