Load-Controlled Compression of Articular Cartilage Induces a Transient Stimulation of Aggrecan Gene Expression

Valhmu, Wilmot B.; Stazzone, Enrico J.; Bachrach, Nathaniel; Saed‐Nejad, Fatemeh; Fischer, Stuart G.; Mow, Van C.; Ratcliffe, Anthony

doi:10.1006/abbi.1998.0633

Cited by 136 publications

(104 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In bovine articular cartilage explants, low-level compressive loading was found to transiently elevate mRNA levels of aggrecan via a cAMP-dependent mechanism; however, no direct evidence concerning the putative link between PKA and mechanotransduction was established [46]. The role of elevated cAMP levels (and the possible involvement of PKA) in mechanotransduction pathways of bovine articular chondrocytes is also discussed in another study [2].…”

Section: Discussionmentioning

confidence: 99%

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Juhász

Matta

Somogyi

et al. 2014

Cellular Signalling

View full text Add to dashboard Cite

Biomechanical stimuli play important roles in the formation of articular cartilage during early foetal life, and optimal mechanical load is a crucial regulatory factor of adult chondrocyte metabolism and function. In this study, we undertook to analyse mechanotransduction pathways during in vitro chondrogenesis. Chondroprogenitor cells isolated from limb buds of 4-day-old chicken embryos were cultivated as high density cell cultures for 6 days. Mechanical stimulation was carried out by a self-designed bioreactor that exerted uniaxial intermittent cyclic load transmitted by the culture medium as hydrostatic pressure and fluid shear to differentiating cells. The loading scheme (0.05 Hz, 600 Pa; for 30 min) was applied on culturing days 2 and 3, when final commitment and differentiation of chondroprogenitor cells occurred in this model. The applied mechanical load significantly augmented cartilage matrix production and elevated mRNA expression of several cartilage matrix constituents, including collagen type II and aggrecan core protein, as well as matrixproducing hyaluronan synthases through enhanced expression, phosphorylation and nuclear signals of the main chondrogenic transcription factor Sox9. Along with increased cAMP levels, a significantly enhanced protein kinase A (PKA) activity was also detected and CREB, the archetypal downstream transcription factor of PKA signalling, exhibited elevated phosphorylation levels and stronger nuclear signals in response to mechanical stimuli. All the above effects were diminished by the PKA-inhibitor H89. Inhibition of the PKA-independent cAMP-mediators Epac1 and Epac2 with HJC0197 resulted in enhanced cartilage formation, which was additive to that of the mechanical stimulation, implying that the chondrogenesispromoting effect of mechanical load was independent of Epac. At the same time, PP2A activity was reduced following mechanical load and treatments with the PP2A-inhibitor okadaic acid were able to mimic the effects of the intervention. Our results indicate that proper mechanical stimuli augment in vitro cartilage formation via promoting both Juhász and Matta et al. 3 differentiation and matrix production of chondrogenic cells, and the opposing regulation of the PKA/CREB-Sox9 and the PP2A signalling pathways is crucial in this phenomenon.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Juhász

Matta

Somogyi

et al. 2014

Cellular Signalling

View full text Add to dashboard Cite

show abstract

“…23,24 The chondrocytes respond to the mechanical stimuli by multiple regulatory pathways, with consequences on transcription, translation and post-translational modifications that further control extra cellular matrix production and function. 4,34 Integrins, growth factor receptors, cytoskeletal filaments, nuclei, stretch-activated ion channels and cartilage ECM proteins are just some of the signaling molecules that contribute to biosynthesis, remodeling, or repair of the tissue as mechanotransduction response to mechanical loading. 14,15 Tissue Engineering is an integrative area of biotechnology and engineering that 3 focuses on restoring or improving tissue function with cells and materials.…”

Section: Introductionmentioning

confidence: 99%

Local deformation in a hydrogel induced by an external magnetic field

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Injurious compression of cartilage explants results in increased PG loss to medium and damage to the collagen network (12, 13). Currently, many cartilage tissue engineering strategies employ some form of mechanical stimulation to enhance matrix production by chondrocytes during culture (14 -18).Recent studies of mechano-regulation of chondrocyte gene expression showed that application of 25-50% static compression to bovine cartilage explants caused a transient increase in expression of aggrecan (19,20) and type II collagen (19) mRNA levels during the first 4 h of loading (Ͼ1.5-fold), followed by a …”

mentioning

confidence: 99%

Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

Fitzgerald

Jin

Dean

et al. 2004

Journal of Biological Chemistry

224

184

View full text Add to dashboard Cite

Chondrocytes are influenced by mechanical forces to remodel cartilage extracellular matrix. Previous studies have demonstrated the effects of mechanical forces on changes in biosynthesis and mRNA levels of particular extracellular matrix molecules, and have identified certain signaling pathways that may be involved. However, the broad extent and kinetics of mechano-regulation of gene transcription has not been studied in depth. We applied static compressive strains to bovine cartilage explants for periods between 1 and 24 h and measured the response of 28 genes using real time PCR. Compression time courses were also performed in the presence of an intracellular calcium chelator or an inhibitor of cyclic AMP-activated protein kinase A. Cluster analysis of the data revealed four main expression patterns: two groups containing either transiently up-regulated or duration-enhanced expression profiles could each be subdivided into genes that did or did not require intracellular calcium release and cyclic AMP-activated protein kinase A for their mechano-regulation. Transcription levels for aggrecan, type II collagen, and link protein were up-regulated ϳ2-3-fold during the first 8 h of 50% compression and subsequently down-regulated to levels below that of free-swelling controls by 24 h. Transcription levels of matrix metalloproteinases-3, -9, and -13, aggrecanase-1, and the matrix protease regulator cyclooxygenase-2 increased with the duration of 50% compression 2-16-fold by 24 h. Thus, transcription of proteins involved in matrix remodeling and catabolism dominated over anabolic matrix proteins as the duration of static compression increased. Immediate early genes c-fos and c-jun were dramatically up-regulated 6 -30-fold, respectively, during the first 8 h of 50% compression and remained up-regulated after 24 h. Articular cartilage is responsible for the smooth articulation of synovial joints during locomotion. Chondrocytes within cartilage constantly remodel the extracellular matrix (ECM) 1 of the tissue throughout life. The major load-bearing constituents of the ECM are type II collagen and aggregates of the proteoglycan, aggrecan, which provide the tensile and compressive stiffness of the tissue, respectively. Also present in the ECM are families of matrix proteinases, tissue inhibitors of matrix metalloproteinases (TIMPs), growth factors, and cytokines that together regulate ECM remodeling and turnover in health and disease (1). It is known that mechanical exercise of the knee joint in vivo increases the density of aggrecan in cartilage (2), whereas knee joint inactivity results in decreased aggrecan deposition (3, 4). Traumatic injury to cartilage diminishes mechanical strength and leads to excessive catabolism of the ECM, increasing the risk of osteoarthritis later in life (5).A number of model systems have been developed to simulate various aspects of the mechanical loading forces experienced by articular cartilage in vivo. Compressive and shear forces have been applied to cartilage explants and chondrocyte cul...

show abstract

Load-Controlled Compression of Articular Cartilage Induces a Transient Stimulation of Aggrecan Gene Expression

Cited by 136 publications

References 58 publications

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Local deformation in a hydrogel induced by an external magnetic field

Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

Contact Info

Product

Resources

About