Mechanical compression alters gene expression and extracellular matrix synthesis by chondrocytes cultured in collagen I gels

Hunter, Christopher; Imler, Stacy M.; Malaviya, Prasanna; Nerem, Robert M.; Levenston, Marc E.

doi:10.1016/s0142-9612(01)00245-9

Cited by 152 publications

(103 citation statements)

References 57 publications

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“…Results using competitive and real-time PCR showed inhibition of type I collagen, type II collagen, and aggrecan mRNA expression. Radiolabel incorporation of proline and sulfate were also inhibited by the application of static compression (42). In both of these experiments, changes in mRNA expression levels correlated with changes occurring at the protein level.…”

Section: Discussionmentioning

confidence: 77%

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Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Lee

Fitzgerald

DiMicco

et al. 2005

Arthritis & Rheumatism

199

172

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Objective. Joint injury in young adults leads to an increased risk of developing osteoarthritis (OA) later in life. This study was undertaken to determine if injurious mechanical compression of cartilage explants results in changes at the level of gene transcription that may lead to subsequent degradation of the cartilage.Methods. Cartilage was explanted from the femoropatellar groove of newborn calves. Levels of messenger RNA encoding matrix molecules, proteases, their natural inhibitors, transcription factors, and cytokines were assessed in free swelling control cultures as compared with cartilage cultures at 1, 2, 4, 6, 12, and 24 hours after application of a single injurious compression.Results. Gene-expression levels measured in noninjured, free swelling cartilage varied over 5 orders of magnitude. Matrix molecules were the most highly expressed of the genes tested, while cytokines, matrix metalloproteinases (MMPs), aggrecanases (ADAMTS-5), and transcription factors showed lower expression levels. Matrix molecules showed little change in expression after injurious compression, whereas MMP-3 increased ϳ250-fold, ADAMTS-5 increased ϳ40-fold, and tissue inhibitor of metalloproteinases 1 increased ϳ12-fold above the levels in free swelling cultures. Genes typically used as internal controls, GAPDH and ␤-actin, increased expression levels ϳ4-fold after injury, making them unsuitable for use as normalization genes in this study. The expression levels of tumor necrosis factor ␣ and interleukin-1␤, cytokines known to be involved in the progression of OA, did not change in the chondrocytes after injury. Conclusion.Changes in the level of gene expression after mechanical injury are gene specific and time dependent. The quantity of specific proteins may be altered as a result of these changes in gene expression, which may eventually lead to degradation at the tissue level and cause a compromise in cartilage structure and function.

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Section: Discussionmentioning

confidence: 77%

“…Primary chondrocytes were seeded in type I collagen gels and subjected to static compression of 0%, 25%, or 50% for up to 24 hours (42). Results using competitive and real-time PCR showed inhibition of type I collagen, type II collagen, and aggrecan mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Lee

Fitzgerald

DiMicco

et al. 2005

Arthritis & Rheumatism

199

172

View full text Add to dashboard Cite

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“…Disruption of this mechanism may contribute to the phenotype of primary OA. Compressive stress plays a role in chondrocyte metabolism and development (34,35). LRCH1 may play a role in this signaling pathway, such that chondrocytes do not respond normally to compressive stress, which leads to the changes in cartilage composition and structure that are characteristic of OA.…”

Section: Discussionmentioning

confidence: 99%

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

Spector¹,

Reneland²,

Mah³

et al. 2006

Arthritis & Rheumatism

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Objective. To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee.Methods. We examined >25,000 SNPs located within ϳ14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression.Results. The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in casecontrol samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role.Conclusion. A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.Osteoarthritis (OA) is a degenerative joint disease that primarily affects the knees, hips, hands, and spine (1). The biology and epidemiology of OA seem to differ between sites, with a different balance of risk factors and age at onset for different sites. For genetic purposes, site-specific classification is likely to be important, with differential linkage and association results for the hip and the spine (2).

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“…The molecular effects of compressive forces on gene expression in chondrocytes has been studied using several different models, largely ex vivo, including cartilage explants [3][4][5][6][7][8] and in vitro systems such as agarose, 9-11 alginate, 5 and other polymeric scaffolds. [12][13][14] Although the cartilage explant tissue models provide exceptional physiologic simulation of in vivo biomechanics, the tissue-level environment and signaling complexity creates challenges for dissecting the individual molecular responses to the applied compressive forces. The gene expression in chondrocytes under compression is dependent on the magnitude, 3,8,12 frequency, 10 and duration 5,6,8,10,12,13,15 of applied compressive forces.…”

Section: A Compressive Forces Regulate Cartilage Damage and Repairmentioning

confidence: 99%

“…[12][13][14] Although the cartilage explant tissue models provide exceptional physiologic simulation of in vivo biomechanics, the tissue-level environment and signaling complexity creates challenges for dissecting the individual molecular responses to the applied compressive forces. The gene expression in chondrocytes under compression is dependent on the magnitude, 3,8,12 frequency, 10 and duration 5,6,8,10,12,13,15 of applied compressive forces. Dynamic compression of cartilage explant cultures at low magnitudes (3%-5% strain), whether intermittent or periodic, leads to cyclic changes in pressure, deformation, and fluid flow in the cartilage.…”

Section: A Compressive Forces Regulate Cartilage Damage and Repairmentioning

confidence: 99%

Regulation of Chondrocytic Gene Expression by Biomechanical Signals

Knobloch

Madhavan

Nam

et al. 2008

Crit Rev Eukar Gene Expr

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Cartilage is a mechanosensitive tissue, which can means that it can perceive and respond to biomechnical signals. Despite the known importance of biomechanical signals in the etiopathogenesis of arthritic diseases, and their effectiveness in joint restoration, little is understood about their actions at the cellular level. Recent molecular approaches have revealed that specific biomechanical stimuli and cell interactions generate intracellular signals that are powerful inducers or suppressors of proinflammatory and reparative genes in chondrocytes. Biomechanical signals are perceived by cartilage in magnitude-, frequency-, and time-dependent manners. Static and dynamic biomechanical forces of high magnitudes induce proinflammatory genes and inhibit matrix synthesis. Contrarily, dynamic biomechanical signals of low/physiologic magnitudes are potent antiinflammatory signals that inhibit interleukin-1β (IL-1β)-induced proinflammatory gene transcription and abrogate IL-1β/tumor necrosis factor-α-induced inhibition of matrix synthesis. Recent studies have identified nuclear factor-κB (NF-κB) transcription factors as key regulators of biomechanical signal-mediated proinflammatory and antiinflammatory actions. These signals intercept multiple steps in the NF-κB signaling cascade to regulate cytokine gene expression. Taken together, these findings provide insight into how biomechanical signals regulate inflammatory and reparative gene transcription, underscoring their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints.

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Mechanical compression alters gene expression and extracellular matrix synthesis by chondrocytes cultured in collagen I gels

Cited by 152 publications

References 57 publications

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

Regulation of Chondrocytic Gene Expression by Biomechanical Signals

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