Dataset Information

Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone.

ABSTRACT: Loading increases bone mass and strength in a site-specific manner; however, possible effects of loading on bone matrix composition have not been evaluated. Site-specific structural and material properties of mouse bone were analyzed on the macro- and micro/molecular scale in the presence and absence of axial loading. The response of bone to load is heterogeneous, adapting at molecular, micro-, and macro-levels.

Introduction

Osteoporosis is a degenerative disease resulting in reduced bone mineral density, structure, and strength. The overall aim was to explore the hypothesis that changes in loading environment result in site-specific adaptations at molecular/micro- and macro-scale in mouse bone.

Methods

Right tibiae of adult mice were subjected to well-defined cyclic axial loading for 2 weeks; left tibiae were used as physiologically loaded controls. The bones were analyzed with μCT (structure), reference point indentation (material properties), Raman spectroscopy (chemical), and small-angle X-ray scattering (mineral crystallization and structure).

Results

The cranial and caudal sites of tibiae are structurally and biochemically different within control bones. In response to loading, cranial and caudal sites increase in cortical thickness with reduced mineralization (-14 and -3%, p < 0.01, respectively) and crystallinity (-1.4 and -0.3%, p < 0.05, respectively). Along the length of the loaded bones, collagen content becomes more heterogeneous on the caudal site and the mineral/collagen increases distally at both sites.

Conclusion

Bone structure and composition are heterogeneous, finely tuned, adaptive, and site-specifically responsive at the micro-scale to maintain optimal function. Manipulation of this heterogeneity may affect bone strength, relative to specific applied loads.

SUBMITTER: Bergstrom I

PROVIDER: S-EPMC5306148 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone.

Bergström I I Kerns J G JG Törnqvist A E AE Perdikouri C C Mathavan N N Koskela A A Henriksson H B HB Tuukkanen J J Andersson G G Isaksson H H Goodship A E AE Windahl S H SH

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20161205 3

Loading increases bone mass and strength in a site-specific manner; however, possible effects of loading on bone matrix composition have not been evaluated. Site-specific structural and material properties of mouse bone were analyzed on the macro- and micro/molecular scale in the presence and absence of axial loading. The response of bone to load is heterogeneous, adapting at molecular, micro-, and macro-levels.<h4>Introduction</h4>Osteoporosis is a degenerative disease resulting in reduced bone ...[more]

PMID: 27921145

Similar Datasets

Project description:The ability of tissues to sustain and withstand mechanical stress is critical to tissue development and healthy tissue maintenance. The mechanical properties of tissues are typically considered to be dominated by the fibrous extracellular matrix (ECM) component of tissues. Fiber network mechanics can capture certain mechanical features of tissues, such as shear strain stiffening, but is insufficient in describing the compressive response of certain tissues and blood clots that are rich in extracellular matrix. To understand the mechanical response of tissues, we employ a contemporary mechanical model, a fibrous network of fibrin embedded with inert bead inclusions that preserve the volume-conserving constraints of cells in tissues. Combining bulk mechanical rheology and a custom imaging device, we show that the presence of inclusions alters the local dynamic remodeling of the networks undergoing uniaxial compressive strains and demonstrate non-affine correlated motion within a fiber-bead network, predicted to stretch fibers in the network and lead to the ability of the network to stiffen under compression, a key feature of real tissues. These findings have important implications for understanding how local structural properties of cells and ECM fibers impact the bulk mechanical response of real tissues. STATEMENT OF SIGNIFICANCE: To understand why real tissue stiffens under compression, we study a model tissue system which also stiffens: a fibrin network embedded with stiff beads. We design a device that images compression of both fiber and fiber-bead networks. Distinct from previous imaging studies, this setup can dynamically capture network deformation on scales larger than single fibers. From the videos, we see fluid flow and network remodeling are both critical to compression behavior. The fiber-bead network has faster fluid flow, reduced network recovery, and correlated motion during network relaxation. We hypothesize that the beads hinder network relaxation of stretched fibers, thus retaining the applied stress and exhibiting stiffening. Our findings reveal important details for modeling tissue mechanics towards optimizing healthcare.

Project description:Introduction: The in vivo tibial loading mouse model has been extensively used to evaluate bone adaptation in the tibia after mechanical loading treatment. However, there is a prevailing assumption that the load is applied axially to the tibia. The aim of this in silico study was to evaluate how much the apparent mechanical properties of the mouse tibia are affected by the loading direction, by using a validated micro-finite element (micro-FE) model of mice which have been ovariectomized and exposed to external mechanical loading over a two-week period. Methods: Longitudinal micro-computed tomography (micro-CT) images were taken of the tibiae of eleven ovariectomized mice at ages 18 and 20 weeks. Six of the mice underwent a mechanical loading treatment at age 19 weeks. Micro-FE models were generated, based on the segmented micro-CT images. Three models using unitary loads were linearly combined to simulate a range of loading directions, generated as a function of the angle from the inferior-superior axis (θ, 0°-30° range, 5° steps) and the angle from the anterior-posterior axis (ϕ, 0°: anterior axis, positive anticlockwise, 0°-355° range, 5° steps). The minimum principal strain was calculated and used to estimate the failure load, by linearly scaling the strain until 10% of the nodes reached the critical strain level of -14,420 με. The apparent bone stiffness was calculated as the ratio between the axial applied force and the average displacement along the longitudinal direction, for the loaded nodes. Results: The results demonstrated a high sensitivity of the mouse tibia to the loading direction across all groups and time points. Higher failure loads were found for several loading directions (θ = 10°, ϕ 205°-210°) than for the nominal axial case (θ = 0°, ϕ = 0°), highlighting adaptation of the bone for loading directions far from the nominal axial one. Conclusion: These results suggest that in studies which use mouse tibia, the loading direction can significantly impact the failure load. Thus, the magnitude and direction of the applied load should be well controlled during the experiments.

Project description:Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NFκB) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NFκB and induced the expression of NFκB target genes for inflammation and matrix degradation (i.e., IL1β and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NFκB pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1β and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NFκB p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NFκB p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NFκB p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NFκB-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA.

Dataset Information

Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone.

Introduction

Methods

Results

Conclusion

Publications

Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets