Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model

Thompson, William R.; Uzer, Gunes; Brobst, Kaitlyn E.; Sen, Buer; Yen, Sherwin S.; Styner, Martin; Rubin, Janet

doi:10.1038/srep11049

Cited by 41 publications

(50 citation statements)

References 44 publications

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“…In contrast to our results, Lau et al reported an approximately 30% reduction in RANKL gene expression in osteocyte‐like cells after 1 h of vibration (0.3 g, 30 Hz) . In another study using stem‐cell‐derived‐osteocytes, no effect on RANKL expression was found with 2 days of vibration exposure (0.7 g, 90 Hz, 20 min/day) . One possible explanation for this discrepancy can be the different exposure time administered to the cells.…”

Section: Discussioncontrasting

confidence: 99%

“…53 In another study using stem-cell-derived-osteocytes, no effect on RANKL expression was found with 2 days of vibration exposure (0.7 g, 90 Hz, 20 min/day). 54 One possible explanation for this discrepancy can be the different exposure time administered to the cells. A decreased RANKL expression was also observed in our study after day 1 of vibration exposure (data not shown).…”

Section: Administration Duration Influences the Effectsmentioning

confidence: 99%

See 1 more Smart Citation

Administration duration influences the effects of low‐magnitude, high‐frequency vibration on ovariectomized rat bone

Qing

Xie

Liem

et al. 2015

Journal Orthopaedic Research

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Low-magnitude, high-frequency vibration (LMHFV) has been proposed as a non-drug anti-osteoporosis treatment. However, the influence of administration duration on its effect is seldom investigated. In this study, the effect of 16-week LMHFV (0.3 g, 30 Hz, 20 min/day) on the bone mineral densities (BMDs), bone mechanical properties, and cellular responses of osteoporotic and healthy rats was examined by in vivo peripheral quantitative computed tomography (pQCT), fracture tests, cell assays, and mRNA quantification. Forty-eight adult rats were equally assigned to sham surgery (SHM), sham surgery with LMHFV (SHMþV), ovariectomy (OVX), and ovariectomy with LMHFV (OVXþV) groups. At week 8, LMHFV ameliorated ovariectomy-induced deterioration of trabecular bone, with a significantly higher tibia trabecular BMD (þ11.2%) being noted in OVXþV rats (vs. OVX). However, this positive effect was not observed at later time points. Furthermore, 16 weeks of LMHFV caused significant reductions in the vertebral mean BMD (À13.0%), trabecular BMD (À15.7%), and maximum load (À21.5%) in OVXþV rats (vs. OVX). Osteoblasts derived from osteoporotic rat bone explants showed elevated BSP and OSX mRNA expression induced by LMHFV on day 1. However, no further positive effect on osteoblastic mRNA expression, alkaline phosphatase activity, or calcium deposition was observed with prolonged culture time. A higher ratio of RANKL/OPG induced by LMHFV suggests that osteoclastogenesis may be activated. Together, these results demonstrate that administration duration played an important role in the effect of LMHFV. Early exposure to LMHFV can positively modulate osteoporotic bone and osteoblasts; however, the beneficial effect seems not to persist over time. Osteoporotic fracture is a significant cause of morbidity and mortality in the elderly.1 As a mechanosensitive tissue, bone adapts its mass, microstructure, and strength in response to dynamic mechanical loading. Hence, people with osteoporosis are encouraged to exercise their musculoskeletal system, as bone mineral density (BMD) can be improved by moderate-to-high-intensity weight-bearing physical activity.2,3 However, few elderly individuals are able to undertake these exercises. One possible alternative modality is low-magnitude, high-frequency vibration (LMHFV), which is performed in a low-impact manner with the possibility of producing results similar to those of physical exercises.4,5 A precursory study in 2001 reported the powerful osteogenic potential of LMHFV, in which the hind limbs of ovine were subjected to mechanical vibration (30 Hz, 0.3 g) resulting in a 34% higher trabecular bone density in the proximal femur compared with that in the control.6 LMHFV has been proposed as a non-pharmacological approach for the prevention and treatment of osteoporosis in elderly postmenopausal women. 7-9Scientific research with respect to LMHFV has been prolific in the past decade. However, initial attempts to stimulate osteoporotic bone formation using this approach have not been uniformly...

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Section: Discussioncontrasting

confidence: 99%

Section: Administration Duration Influences the Effectsmentioning

confidence: 99%

Administration duration influences the effects of low‐magnitude, high‐frequency vibration on ovariectomized rat bone

Qing

Xie

Liem

et al. 2015

Journal Orthopaedic Research

View full text Add to dashboard Cite

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“…2E). In fact, osteocytic genes shared with MSC-B7 and MSC-B15 cells were further increased in the MSC-B15 cells, suggesting that by day 15, the MSCs were either progressing toward or had become osteocytes, as recently suggested (39). Interestingly, gremlin-1 (Grem1) expression was identified following osteoblast differentiation; Grem1-positive MSCs are hypothesized to be unable to differentiate into adipocytes (40).…”

Section: Marrow-derived Mscs Differentiate Into Mature Adipocytes Andmentioning

confidence: 72%

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Meyer

Benkusky

Sen

et al. 2016

Journal of Biological Chemistry

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154

124

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Terminal differentiation of multipotent stem cells is achieved through a coordinated cascade of activated transcription factors and epigenetic modifications that drive gene transcription responsible for unique cell fate. Within the mesenchymal lineage, factors such as RUNX2 and PPAR␥ are indispensable for osteogenesis and adipogenesis, respectively. We therefore investigated genomic binding of transcription factors and accompanying epigenetic modifications that occur during osteogenic and adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (MSCs). As assessed by ChIP-sequencing and RNA-sequencing analyses, we found that genes vital for osteogenic identity were linked to RUNX2, C/EBP␤, retinoid X receptor, and vitamin D receptor binding sites, whereas adipocyte differentiation favored PPAR␥, retinoid X receptor, C/EBP␣, and C/EBP␤ binding sites. Epigenetic marks were clear predictors of active differentiation loci as well as enhancer activities and selective gene expression. These marrow-derived MSCs displayed an epigenetic pattern that suggested a default preference for the osteogenic pathway; however, these patterns were rapidly altered near the Adipoq, Cidec, Fabp4, Lipe, Plin1, Pparg, and Cebpa genes during adipogenic differentiation. Surprisingly, we found that these cells also exhibited an epigenetic plasticity that enabled them to transdifferentiate from adipocytes to osteoblasts (and vice versa) after commitment, as assessed by staining, gene expression, and ChIP-quantitative PCR analysis. The osteogenic default pathway may be subverted during pathological conditions, leading to skeletal fragility and increased marrow adiposity during aging, estrogen deficiency, and skeletal unloading. Taken together, our data provide an increased mechanistic understanding of the epigenetic programs necessary for multipotent differentiation of MSCs that may prove beneficial in the development of therapeutic strategies.

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“…Osteocytes, the mechanosensors in bone, have also been demonstrated to be affected by LMHF vibration. For instance, the gap junctional communication of MLO‐Y4 osteocytes is amplified by low‐intensity vibration (Uzer et al, ), and the expression of some osteocyte markers, such as sclerostin and RANKL, was also changed after low‐magnitude vibration (Lau et al, ; Thompson et al, ). Moreover, the osteoclasts resorption is inhibited by the control medium of vibrated osteocytes (Lau et al, ).…”

Section: Introductionmentioning

confidence: 99%

The bio‐response of osteocytes and its regulation on osteoblasts under vibration

Sun

et al. 2016

Cell Biology International

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Vibration, especially at low magnitude and high frequency (LMHF), was demonstrated to be anabolic for bone, but how the LMHF vibration signal is perceived by osteocytes is not fully studied. On the other hand, the mechanotransduction of osteocytes under shear stress has been scientists' primary focus for years. Due to the small strain caused by low-magnitude vibration, whether the previous explanation for shear stress will still work for LMHF vibration is unknown. In this study, a finite element method (FEM) model based on the real geometrical shape of an osteocyte was built to compare the mechanical behaviors of osteocytes under LMHF vibration and shear stress. The bio-response of osteocytes to vibration under different frequencies, including the secretion of soluble factors and the concentration of intracellular calcium, were studied. The regulating effect of the conditioned medium (CM) from vibrated osteocytes on osteoblasts was also studied. The FEM analysis result showed the cell membrane deformation under LMHF vibration was very small (with a peak value of 1.09%) as compared to the deformation caused by shear stress (with a peak value of 6.65%). The F-actin stress fibers of osteocytes were reorganized, especially on the nucleus periphery after LMHF vibration. The vibration at 30 Hz has a promoting effect on osteocytes and the osteogenesis of osteoblasts, whereas vibration at 90 Hz was suppressive. These results lead to a conclusion that the bio-response of osteocytes to LMHF vibration is frequency-dependent and is more related to the cytoskeleton on nuclear periphery rather than the membrane deformation.

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Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model

Cited by 41 publications

References 44 publications

Administration duration influences the effects of low‐magnitude, high‐frequency vibration on ovariectomized rat bone

Administration duration influences the effects of low‐magnitude, high‐frequency vibration on ovariectomized rat bone

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

The bio‐response of osteocytes and its regulation on osteoblasts under vibration

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