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Time-dependent nanomechanics of cartilage.

ABSTRACT: In this study, atomic force microscopy-based dynamic oscillatory and force-relaxation indentation was employed to quantify the time-dependent nanomechanics of native (untreated) and proteoglycan (PG)-depleted cartilage disks, including indentation modulus E(ind), force-relaxation time constant ?, magnitude of dynamic complex modulus |E(?)|, phase angle ? between force and indentation depth, storage modulus E', and loss modulus E?. At ?2 nm dynamic deformation amplitude, |E(?)| increased significantly with frequency from 0.22 ± 0.02 MPa (1 Hz) to 0.77 ± 0.10 MPa (316 Hz), accompanied by an increase in ? (energy dissipation). At this length scale, the energy dissipation mechanisms were deconvoluted: the dynamic frequency dependence was primarily governed by the fluid-flow-induced poroelasticity, whereas the long-time force relaxation reflected flow-independent viscoelasticity. After PG depletion, the change in the frequency response of |E(?)| and ? was consistent with an increase in cartilage local hydraulic permeability. Although untreated disks showed only slight dynamic amplitude-dependent behavior, PG-depleted disks showed great amplitude-enhanced energy dissipation, possibly due to additional viscoelastic mechanisms. Hence, in addition to functioning as a primary determinant of cartilage compressive stiffness and hydraulic permeability, the presence of aggrecan minimized the amplitude dependence of |E(?)| at nanometer-scale deformation.

SUBMITTER: Han L

PROVIDER: S-EPMC3072655 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

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Time-dependent nanomechanics of cartilage.

Han Lin L Frank Eliot H EH Greene Jacqueline J JJ Lee Hsu-Yi HY Hung Han-Hwa K HH Grodzinsky Alan J AJ Ortiz Christine C

Biophysical journal 20110401 7

In this study, atomic force microscopy-based dynamic oscillatory and force-relaxation indentation was employed to quantify the time-dependent nanomechanics of native (untreated) and proteoglycan (PG)-depleted cartilage disks, including indentation modulus E(ind), force-relaxation time constant τ, magnitude of dynamic complex modulus |E(∗)|, phase angle δ between force and indentation depth, storage modulus E', and loss modulus E″. At ∼2 nm dynamic deformation amplitude, |E(∗)| increased signific ...[more]

PMID: 21463599

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Project description:Objective. Exercise is crucial for maintaining cartilage integrity and providing prophylaxis against the onset of osteoarthritis (OA). Here we systematically examined the exercise driven transcriptional activation/repression of genes from healthy articular cartilage to dissect the metabolic pathways responsible for its potential benefits. Methods. Healthy Sprague-Dawley rats were either not exercised (control) or subjected to daily exercise (low intensity treadmill walking) for 2, 5, or 15 days. Subsequently, articular cartilage from distal femoral heads was harvested, RNA extracted and the transcriptome-wide regulation of gene expression analyzed by Affymetrix microarray chips. Kyoto Encyclopedia of Genes and Genome (KEGG) database was used to identify the metabolic pathways regulated by exercise. Results. Microarray analysis of articular cartilage from exercised rats revealed two fold or greater up or down regulation of 926 transcripts for up to 15 days, as compared to control rat cartilage. The KEGG pathway analysis revealed that exercise transcriptionally activates/suppresses genes that encode proteins involved in regulating 123 metabolic pathways. These pathways control the biosynthesis of molecules associated with extracellular matrix, intermediate metabolites, cell signaling, cell growth and differentiation, cytoskeletal rearrangements, and inflammation including those associated with OA. Conclusions. Our findings highlight that exercise is a robust transcriptional regulator of a wide array of genes in the healthy cartilage. The actions of exercise collectively regulate metabolic pathways that are critical for strengthening cartilage while attenuating detrimental effects of proteolytic enzymes and inflammatory pathways to provide prophylaxis against inflammatory joint diseases. Sprague Dawley rats (n=5 per group, 12-14 weeks old females, Harlan Labs, IN) were housed at 5 animals/cage in individually ventilated cages with sterile Aspen bedding, and standard environmental enrichment. The cages were maintained at 12-h light/12-h dark cycle at 21Â°C in a pathogen free unit. All rats had ad libitum access to water and food and allowed normal cage activity. Animals randomly assigned to each group were either not exercised (Controls/Group I) or exercised (treadmill walking, 12 m/min for 45 min daily) for 2 (Group II), 5 (Group III), or 15 (Group IV) days13. Articular cartilage on the condyles of distal femurs were carefully dissected on ice under a stereomicroscope (10â15 mg/femur), immediately placed on dry ice and pulverized (3x30 seconds at 2500 RPM) in a Mikrodismembrator S (Sartorius, Germany). RNA was extracted using Trizol reagent (Invitrogen, CA), and RNA quality verified by a Bioanalyzer 2100 (Agilent, CA)13. The Whole Transcript (WT) cDNA Synthesis and Amplification Kit and WT Terminal Labeling Kit (Affymetrix, CA) were used for cDNA synthesis and labeling from 300 ng RNA template as recommended by the manufacturers. Labeled samples from 3 different rats from each group were hybridized to Affymetrix GeneChip Rat Gene 1.0 ST Array and scanned with GeneChip Scanner 3000 7G System (Microarray Shared Resource Facility, OSU Comprehensive Cancer Center)13.

Project description:To determine changes in chondrocyte transcription of a range of anabolic, catabolic and signaling genes following simultaneous treatment of cartilage with Insulin-like growth factor-1 (IGF-1) and ramp-and-hold mechanical compression, and compare with effects on biosynthesis.Explant disks of bovine calf cartilage were slowly compressed (unconfined) over 3-min to their 1mm cut-thickness (0%-compression) or to 50%-compression with or without 300 ng/ml IGF-1. Expression of 24 genes involved in cartilage homeostasis was measured using qPCR at 2, 8, 24, 32, 48 h after compression +/-IGF-1. Clustering analysis was used to identify groups of co-expressed genes to further elucidate mechanistic pathways.IGF-1 alone stimulated gene expression of aggrecan and collagen II, but simultaneous 24h compression suppressed this effect. Compression alone up-regulated expression of matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5 and transforming growth factor (TGF)-beta, an effect not reversed by simultaneous IGF-1 treatment. Temporal changes in expression following IGF-1 treatment were generally slower than that following compression. Clustering analysis revealed five distinct groups within which the pairings, tissue inhibitor of metalloproteinase (TIMP)-3 and ADAMTS-5, MMP-1 and IGF-2, and IGF-1 and Collagen II, were all robustly co-expressed, suggesting inherent regulation and feedback in chondrocyte gene expression. While aggrecan synthesis was transcriptionally regulated by IGF-1, inhibition of aggrecan synthesis by sustained compression appeared post-transcriptionally regulated.Sustained compression markedly altered the effects of IGF-1 on expression of genes involved in cartilage homeostasis, while IGF-1 was largely unable to moderate the transcriptional effects of compression alone. The demonstrated co-expressed gene pairings suggest a balance of anabolic and catabolic activity following simultaneous mechanical and growth factor stimuli.

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Time-dependent nanomechanics of cartilage.

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Time-dependent nanomechanics of cartilage.

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