Rho kinase–dependent CCL20 induced by dynamic compression of human chondrocytes

Haudenschild, Dominik R.; Nguyen, Bao Trong; Chen, Jian Fei; D’Lima, Darryl D.; Lotz, Martin

doi:10.1002/art.23797

Cited by 38 publications

(30 citation statements)

References 73 publications

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“…49 We also see an increased expression by day 7, which indicates that the conditions created in the bioreactor were sufficient to generate a mechanoresponsive change. By 14 days, iNOS and CCL20 expression levels were similar to FS gels.…”

Section: Fig 5 Viability Assessment Immunohistochemistry (Ihc)mentioning

confidence: 70%

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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Section: Fig 5 Viability Assessment Immunohistochemistry (Ihc)mentioning

confidence: 70%

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

Grogan

Sovani

Pauli

et al. 2012

Tissue Engineering Part A

Self Cite

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show abstract

“…These data point towards a potentially important role for CCL20 as a mediator of joint inflammation in spondyloarthritis patients. CCL20 is produced locally in the joint by chondrocytes upon exposure to mechanical stress,29 by synovial fibroblasts upon stimulation with proinflammatory cytokines30 and by Th17 cells 31. CCL20 in turn, attracts immature myeloid dendritic cells32 as well as naive B cells33 and effector memory T cells, especially Th17 cells 34…”

Section: Discussionmentioning

confidence: 99%

Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis

Melis

Vandooren

Kruithof

et al. 2010

Annals of the Rheumatic Diseases

132

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“…Previous associated studies in chondrocytes mainly focused on the role of RhoA following mechanical stimulation [30,31]. Haudenschild and colleagues reported that mechanical stimulation activated SOX9 in human chondrocytes and that RhoA signaling plays an important role in that process [30].…”

Section: Discussionmentioning

confidence: 99%

Periodic Mechanical Stress Activates Integrin�1-Dependent Src-Dependent PLC?1-Independent Rac1 Mitogenic Signal in Rat Chondrocytes through ERK1/2

Liu

Huang

Liang

et al. 2012

Cell Physiol Biochem

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The effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively in recent years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to periodic mechanical stress remain a matter of debate. We explored the signal transduction pathways of proliferation and matrix synthesis when chondrocytes were exposed to periodic mechanical stress. We observed that periodic mechanical stress statistically and significantly enhanced the phosphorylation and activation of Rac1 (p<0.05 for each). Pre-treatment with the Rac1 selective inhibitor NSC23766 attenuated periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis (p<0.05 for each) and abrogated ERK1/2 signal activation (p<0.05), but did not block periodic mechanical stressinduced Src and PLCγ1 phosphorylation in this context. In addition, inhibition of Src with its selective inhibitor PP2 and shRNA targeted to Src blocked Rac1 signal activation (p<0.05 for each), but inhibition of the activity of PLCγ1 did not affect the phosphorylation and activation levels of Rac1 under conditions of periodic mechanical stress. The up-regulation of proliferation and matrix synthesis was inhibited in chondrocytes in response to periodic mechanical stress after pretreatment with blocking antibody against integrinβ1 (p<0.05 for each) but not after pretreatment with blocking antibody against integrinβ3. The phosphorylation levels of ERK1/2, Rac1, PLCγ1 and Src, and Rac1 activation level were also reduced when integrinβ1 was blocked in this context (p<0.05 for each). These findings suggest that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis in part by activating the ERK1/2 mitogenic signal through the integrinβ1-Src-PLCγ1/Rac1-ERK1/2 pathway, which links these important signaling molecules into mitogenic cascades.

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Rho kinase–dependent CCL20 induced by dynamic compression of human chondrocytes

Cited by 38 publications

References 73 publications

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

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

Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis

Periodic Mechanical Stress Activates Integrin�1-Dependent Src-Dependent PLC?1-Independent Rac1 Mitogenic Signal in Rat Chondrocytes through ERK1/2

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