Cyclic compressive mechanical stimulation induces sequential catabolic and anabolic gene changes in chondrocytes resulting in increased extracellular matrix accumulation

Croos, J.N. Amritha De; Dhaliwal, Simrit; Grynpas, Marc D.; Pilliar, Robert M.; Kandel, Rita A.

doi:10.1016/j.matbio.2006.03.005

Cited by 117 publications

(100 citation statements)

References 40 publications

(45 reference statements)

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“…In addition, p38 signaling contributes toward transforming growth factor-␤-stimulated proteoglycan synthesis and chondrocyte proliferation (36,37), and ERK1/2 is activated by insulin-like growth factor-1, which strongly promotes anabolic chondrocyte behavior (17,35). It was also shown recently that JNK inhibition during cyclic compression of tissue-engineered constructs prevents up-regulation of aggrecan and type II collagen, as well as MMP3 and MMP13 genes (51). Taken together with our observations of widespread involvement of ERK1/2 and p38 in mechanically induced transcription of matrix proteins, proteases, and TIMPs (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…known to be downstream of the MAPK pathway (20,33). It has been shown that gene expression levels of c-Fos and c-Jun dramatically increase within 1 h of a variety of intact cartilage loading regimens (6,8,41), and that activating protein-1 binding increases in response to dynamic compression of a tissue engineered cartilage construct (51). Furthermore, we found that c-Fos and c-Jun mechano-regulated mRNA levels were partially suppressed by MAPK inhibition, which also suppressed many matrix proteins and proteases (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Shear- and Compression-induced Chondrocyte Transcription Requires MAPK Activation in Cartilage Explants

Fitzgerald

Jin

Chai

et al. 2008

Journal of Biological Chemistry

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Chondrocytes regulate the composition of cartilage extracellular matrix in response to mechanical signals, but the intracellular pathways involved in mechanotransduction are still being defined. Mitogen-activated protein kinase (MAPK) pathways are activated by static and dynamic compression of cartilage, which simultaneously induce intratissue fluid flow, pressure gradients, cell, and matrix deformation. First, to determine whether cell and matrix deformation alone could induce MAPK activation, we applied dynamic shear to bovine cartilage explants. Using Western blotting, we measured ERK1/2 and p38 activation at multiple time points over 24 h. Distinct activation time courses were observed for different MAPKs: a sustained 50% increase for ERK1/2 and a delayed increase in p38 of 180%. We then investigated the role of MAPK activation in mechano-induced chondrocyte gene expression. Cartilage explants were preincubated with inhibitors of ERK1/2 and p38 activation before application of 1-24 h of three distinct mechanical stimuli relevant to in vivo loading (50% static compression, 3% dynamic compression at 0.1 Hz, or 3% dynamic shear at 0.1 Hz). mRNA levels of selected genes involved in matrix homeostasis were measured using realtime PCR and analyzed by k-means clustering to characterize the time-and load-dependent effects of the inhibitors. Most genes examined required ERK1/2 and p38 activation to be regulated by these loading regimens, including matrix proteins aggrecan and type II collagen, matrix metalloproteinases MMP13, and ADAMTS5, and transcription factors downstream of the MAPK pathway, c-Fos, and c-Jun. Thus, we demonstrated that the MAPK pathway is a central conduit for transducing mechanical forces into biological responses in cartilage.In vitro models of chondrocyte mechanobiology relevant to physiological loading of cartilage in vivo have shown that biosynthesis and gene transcription of the major matrix proteins in cartilage are regulated by distinct tissue deformations (reviewed in Ref. 1). Application of static compression to intact cartilage explants is inhibitory to proteoglycan and type II collagen production and transcription (2-7), whereas dynamic loading regimens, including dynamic compression and dynamic shear deformation, generally enhance matrix protein biosynthesis and transcription (4, 8 -13). Differences in intracellular signaling between normal and osteoarthritic chondrocytes following mechanical loading (14 -16) have led to speculation that altered mechanotransduction may be a cause or result of the development of osteoarthritis following injury. Therefore, understanding the pathway(s) by which chondrocytes transduce mechanical forces into biological responses is of great importance to the treatment of osteoarthritis and to cartilage tissue engineering. The mitogen-activated protein kinase (MAPK) 5 pathway has been implicated in chondrocyte mechanotransduction responses. In cartilage explants, static compression can induce the phosphorylation of extracellular signal-regulated kinases ...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Shear- and Compression-induced Chondrocyte Transcription Requires MAPK Activation in Cartilage Explants

Fitzgerald

Jin

Chai

et al. 2008

Journal of Biological Chemistry

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“…In a majority of studies, mechanical stimulation, whether applied through direct mechanical compression [3][4][5][6][7][8][9][10][11] or via hydrostatic means, 12,13 has improved extracellular matrix (ECM) deposition (principally proteoglycans) and the mechanical properties of the engineered cartilage. While dynamic compressive load may stimulate ECM production, this stimulus may also reduce accumulation or increase loss of newly secreted ECM into the medium in comparison to freeswelling (FS) or unloaded conditions.…”

Section: Introductionmentioning

confidence: 99%

Effects of Perfusion and Dynamic Loading on Human Neocartilage Formation in Alginate Hydrogels

Grogan

Sovani

Pauli

et al. 2012

Tissue Engineering Part A

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Dynamic loading and perfusion culture environments alone are known to enhance cartilage extracellular matrix (ECM) production in dedifferentiated articular chondrocytes. In this study, we explored whether a combination of these factors would enhance these processes over a free-swelling (FS) condition using adult human articular chondrocytes embedded in 2% alginate. The alginate constructs were placed into a bioreactor for perfusion (P) only (100 mL/per minute) or perfusion and dynamic compressive loading (PL) culture (20% for 1 h, at 0.5 Hz), each day. Control FS alginate gels were maintained in six-well static culture. Gene expression analysis was conducted on days 7 and 14, while cell viability, immunostaining, and mechanical property testing were performed on day 14 only. Total glycosaminoglycan (GAG) content and GAG synthesis were assessed after 14 days. Col2a1 mRNA expression levels were significantly higher (at least threefold; p < 0.05) in both bioreactor conditions compared with FS by days 7 and 14. For all gene studies, no significant differences were seen between P and PL treatments. Aggrecan mRNA levels were not significantly altered in any condition although both GAG/ DNA and 35 S GAG incorporation studies indicated higher GAG retention and synthesis in the FS treatment. Collagen type II protein deposition was low in all samples, link protein distribution was more diffuse in FS condition, and aggrecan deposition was located in the outer regions of the alginate constructs in both bioreactor conditions, yet more uniformly in the FS condition. Catabolic gene expression (matrix metalloproteinase 3 [MMP3] and inducible nitric oxide synthase [iNOS]) was higher in bioreactor conditions compared with FS, although iNOS expression levels decreased to approximately fourfold less than the FS condition by day 14. Our data indicate that conditions created in the bioreactor enhanced both anabolic and catabolic responses, similar to other loading studies. Perfusion was sufficient alone to promote this dual response. PL increased the deposition of aggrecan surrounding cells compared with the other conditions; however, overall low GAG retention in the bioreactor system was likely due to both perfusion and catabolic conditions created. Optimal conditions, which permit appropriate anabolic and catabolic processes for accumulation of ECM and tissue remodeling for neocartilage development, specifically for humans, are needed.

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“…The MAPK family has three important members, namely, extracellular signal-regulated kinases (ERK)-1/2 (ERK1/2), c-Jun aminoterminal kinases (JNK), and p38 MAPK (Seger and Krebs, 1995). Studies on MAPKs in several types of cells have indicated that pathway activation occurs after loading stimulation (Hofmann et al, 2004;De Croos et al, 2006). Induction of various extracellular signal transduction pathways, which regulate morphology, proliferation, differentiation, or survival, triggers the activation of at least one MAPK (Peyssonnaux and Eychène, 2001;Volmat and Pouysségur, 2001).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the MAPK pathway in the pressure-induced synovial metaplasia procedure for the temporomandibular joint

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Abnormal pressure is an important factor that contributes to bone adaptation in the temporomandibular joint (TMJ). We determined the effect of the mitogen-activated protein kinases (MAPK) pathway on the pressure-induced synovial metaplasia procedure for the TMJ, both in vitro and in vivo. Synovial fibroblasts (SFs) were exacted from rat TMJs and exposed to different hydrostatic pressures. The protein extracts were analyzed to determine the activation of ERK1/2, JNK, and p38. Surgical anterior disc displacement (ADD) was also performed on Japanese rabbits, and the proteins of TMJ were isolated to analyze pressure-induced MAPK activation after 1, 2, 4, and 8 weeks. The results showed that the activation of ERK1/2 and JNK in SFs significantly changed with increasing hydrostatic pressure, whereas p38 activation did not change. Moreover, p38 was activated in animals 1 week after surgical ADD. The levels of p38 gradually increased after 2 and 4 weeks, and then slightly decreased but remained higher than in the control 8 weeks after surgical ADD. Nevertheless, JNK was rarely activated after the ADD treatment. Our findings suggest the involvement of MAPK activation in the pressure-induced synovial metaplasia procedure with pressure loading in TMJ.

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Cyclic compressive mechanical stimulation induces sequential catabolic and anabolic gene changes in chondrocytes resulting in increased extracellular matrix accumulation

Cited by 117 publications

References 40 publications

Shear- and Compression-induced Chondrocyte Transcription Requires MAPK Activation in Cartilage Explants

Shear- and Compression-induced Chondrocyte Transcription Requires MAPK Activation in Cartilage Explants

Effects of Perfusion and Dynamic Loading on Human Neocartilage Formation in Alginate Hydrogels

Involvement of the MAPK pathway in the pressure-induced synovial metaplasia procedure for the temporomandibular joint

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