Megakaryocytes are mechanically responsive and influence osteoblast proliferation and differentiation

Soves, Constance Pagedas; Miller, Joshua D.; Begun, Dana L.; Taichman, Russell S.; Hankenson, Kurt D.; Goldstein, Steven A.

doi:10.1016/j.bone.2014.05.015

Cited by 35 publications

(17 citation statements)

References 77 publications

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“…The trabecular pores where the marrow resides are com pressed and expanded during normal mechanical loading, which causes associated motions and stress within the bone. From our results, it can be concluded that if the viscosity of mar row was 5 Pa • s, it would be sufficient to achieve mechanostimulation of marrow cells [42][43][44][45], In a recently published study, the viscosity of bone marrow was highly strain rate dependent, and exceeded 5 Pa • s even at reasonably high strain rates [6]. However, we investigated the potential that the marrow is much more viscous than has been assumed.…”

Section: Discussionmentioning

confidence: 86%

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The In Situ Mechanics of Trabecular Bone Marrow: The Potential for Mechanobiological Response

Metzger

Kreipke

Vaughan

et al. 2015

Journal of Biomechanical Engineering

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Bone adapts to habitual loading through mechanobiological signaling. Osteocytes are the primary mechanical sensors in bone, upregulating osteogenic factors and downregulating osteoinhibitors, and recruiting osteoclasts to resorb bone in response to microdamage accumulation. However, most of the cell populations of the bone marrow niche,which are intimately involved with bone remodeling as the source of bone osteoblast and osteoclast progenitors, are also mechanosensitive. We hypothesized that the deformation of trabecular bone would impart mechanical stress within the entrapped bone marrow consistent with mechanostimulation of the constituent cells. Detailed fluid-structure interaction models of porcine femoral trabecular bone and bone marrow were created using tetrahedral finite element meshes. The marrow was allowed to flow freely within the bone pores, while the bone was compressed to 2000 or 3000 microstrain at the apparent level.Marrow properties were parametrically varied from a constant 400 mPas to a power law rule exceeding 85 Pas. Deformation generated almost no shear stress or pressure in the marrow for the low viscosity fluid, but exceeded 5 Pa when the higher viscosity models were used. The shear stress was higher when the strain rate increased and in higher volume fraction bone. The results demonstrate that cells within the trabecular bone marrow could be mechanically stimulated by bone deformation, depending on deformation rate, bone porosity, and bone marrow properties. Since the marrow contains many mechanosensitive cells, changes in the stimulatory levels may explain the alterations in bone marrow morphology with aging and disease, which may in turn affect the trabecular bone mechanobiology and adaptation.

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Section: Discussionmentioning

confidence: 86%

“…There is a growing body of knowledge implicating the mechanobiology of marrow resident cells of both mesenchymal [40,60] and hematopoietic lineage [28,45,61] in bone and bone marrow maintenance. Unfortunately, bone marrow, due to its location and complex properties, does not easily yield to experimental investi gation.…”

Section: Shear Stress (Pa)mentioning

confidence: 99%

The In Situ Mechanics of Trabecular Bone Marrow: The Potential for Mechanobiological Response

Metzger

Kreipke

Vaughan

et al. 2015

Journal of Biomechanical Engineering

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“…A recent analysis of regions of mechanically induced bone formation in the rodent tail found that stress/strain within the bone marrow was more strongly correlated with locations of new bone formation than stress and strain within the mineralized tissue . Computational models of bone marrow have estimated that fluid shear is of sufficient magnitude to induce an osteogenic response of marrow resident cells …”

Section: Discussionmentioning

confidence: 99%

“…18 Computational models of bone marrow have estimated that fluid shear is of sufficient magnitude to induce an osteogenic response of marrow resident cells. [46][47][48][49] There are several strengths to the current work. First, the current study is novel in using threedimensional imaging to examine the spatial relationships between tissue stress/strain, osteocyte lacunar density, and bone formation.…”

Section: Discussionmentioning

confidence: 99%

Mechanically induced bone formation is not sensitive to local osteocyte density in rat vertebral cancellous bone

Cresswell

Nguyen

Horsfield

et al. 2017

Journal Orthopaedic Research

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Osteocytes play an integral role in bone by sensing mechanical stimuli and releasing signaling factors that direct bone formation. The importance of osteocytes in mechanotransduction suggests that regions of bone tissue with greater osteocyte populations are more responsive to mechanical stimuli. To determine the effects of osteocyte population on bone functional adaptation we applied mechanical loads to the 8th caudal vertebra of skeletally mature female Sprague Dawley rats (6 months of age, n = 8 loaded, n = 8 sham controls). The distribution of tissue stress/strain within cancellous bone was determined using high-resolution finite element models, osteocyte distribution was determined using nano-computed tomography, and locations of bone formation were determined using three-dimensional images of fluorescent bone formation markers. Loading increased bone formation (3D MS/BS 10.82 ± 2.09% in loaded v. 3.17 ± 2.05% in sham control, mean ± SD). Bone formation occurred at regions of cancellous bone experiencing greater tissue stress/strain, however stress/strain was only a modest predictor of bone formation; even at locations of greatest stress/strain the probability of observing bone formation did not exceed 41%. The local osteocyte population was not correlated with locations of new bone formation. The findings support the idea that local tissue stress/strain influence the locations of bone formation in cancellous bone, but suggest that the size of the osteocyte population itself is not influential. We conclude that other aspects of osteocytes such as osteocyte connectivity, lacunocanilicular nano-geometry, and/or fluid pressure/shear distributions within the marrow space may be more influential in regulating bone mechanotransduction than the number of osteocytes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:672-681, 2018.

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“…Osteocyte mechanotransduction is the primary controller of bone adaptation and repair (Bonewald, 2006;Schaffler et al, 2014;You et al, 2008). However, cells in the marrow are also mechanically sensitive (Luu et al, 2009;Qin, 2003;Soves et al, 2014). Indeed, mechanical loading of mouse limbs in vivo induces mechanical signaling between marrow cells (Soves et al, 2014) and increased proliferation and osteogenic gene expression in marrow stromal cells (Li et al, 2004;Mantila Roosa et al, 2011;Ozcivici et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Pressure and shear stress in trabecular bone marrow during whole bone loading

Metzger

Schwaner

LaNeve

et al. 2015

Journal of Biomechanics

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Skeletal adaptation to mechanical loading is controlled by mechanobiological signaling. Osteocytes are highly responsive to applied strains, and are the key mechanosensory cells in bone. However, many cells residing in the marrow also respond to mechanical cues such as hydrostatic pressure and shear stress, and hence could play a role in skeletal adaptation. Trabecular bone encapsulates marrow, forming a poroelastic solid. According to the mechanical theory, deformation of the pores induces motion in the fluid-like marrow, resulting in pressure and velocity gradients. The latter results in shear stress acting between the components of the marrow. To characterize the mechanical environment of trabecular bone marrow in situ, pore pressure within the trabecular compartment of whole porcine femurs was measured with miniature pressure transducers during stress-relaxation and cyclic loading. Pressure gradients ranging from 0.013 to 0.46 kPa/mm were measured during loading. This range was consistent with calculated pressure gradients from continuum scale poroelastic models with the same permeability. Micro-scale computational fluid dynamics models created from computed tomography images were used to calculate the micromechanical stress in the marrow using the measured pressure differentials as boundary conditions. The volume averaged shear stress in the marrow ranged from 1.67 to 24.55 Pa during cyclic loading, which exceeds the mechanostimulatory threshold for mesenchymal lineage cells. Thus, the loading of bone through activities of daily living may be an essential component of bone marrow health and mechanobiology. Additional studies of cell-level interactions during loading in healthy and disease conditions will provide further incite into marrow mechanobiology.

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Megakaryocytes are mechanically responsive and influence osteoblast proliferation and differentiation

Cited by 35 publications

References 77 publications

The In Situ Mechanics of Trabecular Bone Marrow: The Potential for Mechanobiological Response

The In Situ Mechanics of Trabecular Bone Marrow: The Potential for Mechanobiological Response

Mechanically induced bone formation is not sensitive to local osteocyte density in rat vertebral cancellous bone

Pressure and shear stress in trabecular bone marrow during whole bone loading

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