Chondrocyte Migration Affects Tissue-Engineered Cartilage Integration by Activating the Signal Transduction Pathways Involving Src, PLCγ1, and ERK1/2

Lu, Yong; Xu, Yongfen; Yin, Zhaowei; Yang, Xiaofei; Jiang, Yiqiu; Gui, Jian‐Fang

doi:10.1089/ten.tea.2012.0614

Cited by 21 publications

(21 citation statements)

References 22 publications

(27 reference statements)

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“…The average stress value in the regenerated cartilage, 158.0 ± 26.04 kPa, was more than 3 times higher than that reported in comparable studies . This may indicate that increased CPC migration enhanced tissue integration, which is consistent with the results in a study by Lu et al showing that cell migration at the interface of engineered cartilage and surrounding cartilage could result in dramatically stronger host–graft tissue integration after autologous chondrocyte implantation . It is also worth noting that the collagen fiber networks of the regenerated and host tissues in the fully treated defects were extensively entangled with each other, which might explain the gain in integration strength.…”

Section: Discussionsupporting

confidence: 86%

Use of Recombinant Human Stromal Cell–Derived Factor 1α–Loaded Fibrin/Hyaluronic Acid Hydrogel Networks to Achieve Functional Repair of Full‐Thickness Bovine Articular Cartilage Via Homing of Chondrogenic Progenitor Cells

Brouillette

Seol

et al. 2015

Arthritis & Rheumatology

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Objective Articular cartilage damage after joint trauma seldom heals and often leads to osteoarthritis. We previously identified a migratory chondrogenic progenitor cell (CPC) population that responds chemotactically to cell death and rapidly repopulates the injured cartilage matrix, which suggests a potential approach for articular cartilage repair. This study was undertaken to determine whether recombinant human stromal cell–derived factor 1α (rhSDF‐1α), a potent CPC chemoattractant, would improve the quality of cartilage regeneration, hypothesizing that increased recruitment of CPCs by rhSDF‐1α would promote the formation of cartilage matrix upon chondrogenic induction. Methods Full‐thickness bovine chondral defects were filled with hydrogel, composed of fibrin and hyaluronic acid and containing rhSDF‐1α. Cell migration was monitored, followed by chondrogenic induction. Regenerated tissue was evaluated by histology, immunohistochemistry, and scanning electron microscopy. Push‐out tests and unconfined compression tests were performed to assess the strength of tissue integration and the mechanical properties of the regenerated cartilage. Results Use of rhSDF‐1α dramatically improved CPC recruitment to the chondral defects at 12 days. After 6 weeks under chondrogenic conditions, cell morphology, proteoglycan density, and the ultrastructure of the repair tissue were all similar to that found in native cartilage. Compared with empty controls, neocartilage generated in rhSDF‐1α–containing defects showed significantly greater interfacial strength, and acquired mechanical properties comparable to those of native cartilage. Conclusion This study showed that stimulating local CPC recruitment prior to treatment with chondrogenic factors significantly improves the biochemical and mechanical properties of the cartilage tissue formed in chondral defects. This simple approach may be implemented in vivo as a one‐step procedure by staging the release of chemokine and chondrogenic factors from within the hydrogel, which can be achieved using smart drug‐delivery systems.

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Section: Discussionsupporting

confidence: 86%

Use of Recombinant Human Stromal Cell–Derived Factor 1α–Loaded Fibrin/Hyaluronic Acid Hydrogel Networks to Achieve Functional Repair of Full‐Thickness Bovine Articular Cartilage Via Homing of Chondrogenic Progenitor Cells

Brouillette

Seol

et al. 2015

Arthritis & Rheumatology

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“…As one of the important signal molecules, ERK has been known to be involved in multiple signal pathways. Recent study showed that the Src-PLCγ1-ERK1/2 signaling transduction pathway is involved in cartilage tissue integration by affecting chondrocyte migration [ 23 ]. Here, our findings also indicated the existence of the PLCγ1/ERK axis in OA chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Liu

Cai

Zheng

et al. 2015

IJMS

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The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCγ1, p-PLCγ1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCγ1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCγ1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCγ1 on MMP-13 may be partly attributed to the inhibition of the PLCγ1/mTOR axis on the PLCγ1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy.

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“…PLCγ mediated FGFR3-induced STAT1 activation and this signaling cascade involved in the induction of apoptosis in the chondrogenic cell line ATDC5 [ 9 ]. The Src-PLCγ1-ERK1/2 signaling transduction pathway is involved in cartilage tissue integration by affecting chondrocyte migration [ 10 ]. Periodic mechanical stress also promotes chondrocyte proliferation and matrix synthesis in part through the Src-PLCγ1-MEK1/2-ERK1/2 signaling pathway [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

The inhibition of PLCγ1 protects chondrocytes against osteoarthritis, implicating its binding to Akt

Cai

Chen

et al. 2017

Oncotarget

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Previous studies have addressed the involvement of phosphoinositide-specifc phospholipase γ1 (PLCγ1) and protein kinase B (PKB/Akt) in osteoarthritis (OA) pathogenesis, but it is not ascertained the possibility of them to be potential targets for OA therapy. Here, through local intra-articular injection of PLCγ or Akt inhibitor in a rat OA model induced by anterior cruciate ligament transaction plus medial meniscus resection, the architecture of chondrocyte and matrix organization of articular cartilage were observed using histopathological assays and Aggrecan, Col2, PLCγ1, and Akt levels were detected using immunohistochemistry assays. By treatment of Akt or PLCγ inhibitor and transfection of different PLCγ1- or Akt-expressing vectors in rat OA model chondrocytes, Aggrecan, Col2, PLCγ1, p-PLCγ1, Akt, and p-Akt levels were detected using western blotting analysis. The binding between PLCγ1 and Akt was assessed with co-immunoprecipitation assays in human OA chondrocytes. These results showed that PLCγ inhibition protected chondrocytes against OA, but Akt inhibition did not dramatically aggravate OA progression. There were mutual antagonism and binding between PLCγ1 and Akt that could be regulated by their phosphorylation levels. Consequently, the data reveal that the inhibition of PLCγ1 may provide an attractive therapeutic target for OA therapy, implicating its binding to Akt.

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Chondrocyte Migration Affects Tissue-Engineered Cartilage Integration by Activating the Signal Transduction Pathways Involving Src, PLCγ1, and ERK1/2

Cited by 21 publications

References 22 publications

Use of Recombinant Human Stromal Cell–Derived Factor 1α–Loaded Fibrin/Hyaluronic Acid Hydrogel Networks to Achieve Functional Repair of Full‐Thickness Bovine Articular Cartilage Via Homing of Chondrogenic Progenitor Cells

Use of Recombinant Human Stromal Cell–Derived Factor 1α–Loaded Fibrin/Hyaluronic Acid Hydrogel Networks to Achieve Functional Repair of Full‐Thickness Bovine Articular Cartilage Via Homing of Chondrogenic Progenitor Cells

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

The inhibition of PLCγ1 protects chondrocytes against osteoarthritis, implicating its binding to Akt

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