FAK mediates signal crosstalk between type II collagen and TGF-beta 1 cascades in chondrocytic cells

Park, Min Sung; Kim, Yun Hee; Lee, Jin Woo

doi:10.1016/j.matbio.2009.10.001

Cited by 16 publications

(14 citation statements)

References 61 publications

(71 reference statements)

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“…Importantly, we can confirm that PP2 and PF228 also inhibit the activation of Smad2. This is consistent with prior reports demonstrating that anchorage-dependent activation of SFK/ FAK results in the activation of Smad2/3, possibly because of cross-talk between integrins and TGF␤Rs (26,27). In this regard it has been shown that TGF␤1 ligation results in enhanced FAK activation (27).…”

Section: Discussionsupporting

confidence: 93%

“…This is consistent with prior reports demonstrating that anchorage-dependent activation of SFK/ FAK results in the activation of Smad2/3, possibly because of cross-talk between integrins and TGF␤Rs (26,27). In this regard it has been shown that TGF␤1 ligation results in enhanced FAK activation (27). Moreover, it has also been shown that integrin/TGF␤R cross-talk can occur even in the absence of TGF␤ ligation (26).…”

Section: Discussionsupporting

confidence: 92%

“…to promote signaling via the TGF␤R/Smad2/3 axis (26,27). Based on these observations, it is possible that PP2 and PF228 induce endocrine commitment by limiting activation of the Smad2/3 pathway.…”

Section: Inhibition Of C-src Is Sufficient To Induce Ngn3 Expression mentioning

confidence: 97%

“…However, several studies have shown that inhibition of SFK and FAK signaling alters the association between cells and the underlying extracellular matrix, which in turn can have profound consequences for anchorage-dependent growth and differentiation (13,25). Interestingly, anchorage-dependent SFK/ FAK signaling has also been shown to induce the activation of Smad2/3, possibly as a result of cross-talk between integrins and TGF␤ receptors (TGF␤Rs) (26,27). This is significant because TGF␤1-dependent activation of Smad2/3 has also recently been shown to suppress endocrine specification (28,29).…”

mentioning

confidence: 99%

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Inhibitors of Src and Focal Adhesion Kinase Promote Endocrine Specification

Afrikanova

Yebra

Simpkinson

et al. 2011

Journal of Biological Chemistry

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Background: Signaling mechanisms regulating the endocrine specification of stem cell derivatives. Results: Inhibiting Src family kinase (SFK) and focal adhesion kinase (FAK) activity promotes endocrine commitment. Conclusion: Select inhibitors of SFK/FAK signaling increase the derivation of ␤-cells. Significance: Enhanced derivation of insulin-producing ␤-cells for the cell-based therapy of diabetes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Inhibition Of C-src Is Sufficient To Induce Ngn3 Expression mentioning

confidence: 97%

mentioning

confidence: 99%

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Inhibitors of Src and Focal Adhesion Kinase Promote Endocrine Specification

Afrikanova

Yebra

Simpkinson

et al. 2011

Journal of Biological Chemistry

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“…The roles of integrins in osteoblast and chondrocyte differentiation have received intensive investigation. (16)(17)(18)(19)(20) The DDR family is composed of DDR1 and DDR2, which belong to the receptor tyrosine kinase (RTK) family and use collagens as their cognate ligands. A unique feature that distinguishes DDRs from other growth factor receptors is that their maximal activation normally occurs slowly and is sustained for up to 16 hours.…”

Section: Introductionmentioning

confidence: 99%

An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

Zhang

et al. 2010

Journal of Bone and Mineral Research

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Discoidin domain receptor 2 (DDR2) belongs to receptor tyrosine kinase (RTK) family and is activated by collagen binding. Although the bone defects in Ddr2 null mice have been reported for a decade, the molecular mechanism remains unclear. This study sought to investigate the function and detailed mechanism of DDR2 in osteogenic and chondrogenic differentiation. Herein we found that in preosteoblastic cells, DDR2 activation was enhanced by osteogenic induction but was not paralleled with the alteration of DDR2 expression. Under differentiated condition, downregulation of endogenous DDR2 through specific shRNA dramatically repressed osteoblastic marker gene expression and osteogenic differentiation. Enforced expression of constitutively activated DDR2 increased the expression of bone markers in both undifferentiated and differentiated osteoblasts. Importantly, molecular evidence showed that DDR2 regulated the transactivity of Runx2, a master transcription factor involved in skeletal development, by modulating its phosphorylation. Analysis of candidate protein kinases indicated that extracellular signal-regulated kinase (ERK) activation is responsive to DDR2 signaling and involved in DDR2 regulation of Runx2 phosphorylation and transcriptional activity. Notably, a gain-of-function mutant of Runx2 with enhanced ERK-independent phosphorylation rescued the impaired osteogenic phenotypes observed in Ddr2-silenced cells, whereas a Runx2 mutant devoid of phosphorylation regulation by ERK inhibited DDR2 induction of osteogenesis. In addition, DDR2 facilitated Runx2 transactivation and type X collagen expression in hypertrophic chondrocytes. Thus this study reveals for the first time that DDR2 plays an essential role in osteoblast and chondrocyte differentiation. The mechanism disclosure may provide therapeutic targets for human genetic disorders caused by DDR2 deficiency. ß

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TGF β‐1 administration during Ex vivo expansion of human articular chondrocytes in a serum‐free medium redirects the cell phenotype toward hypertrophy

Narcisi

Quarto

Ulivi³

et al. 2012

Journal Cellular Physiology

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Cell-based cartilage resurfacing requires ex vivo expansion of autologous articular chondrocytes. Defined culture conditions minimize expansion-dependent phenotypic alterations but maintenance of the cells' differentiation potential must be carefully assessed. Transforming growth factor β-1 (TGF β-1) positively regulates the expression of several cartilage proteins, but its therapeutic application in damaged cartilage is controversial. Thus we evaluated the phenotypic outcomes of cultured human articular chondrocytes exposed to TGF β-1 during monolayer expansion in a serum-free medium. After five doublings cells were transferred to micromass cultures to assess their chondrogenic differentiation, or replated in osteogenic medium. Immunocytostainings of micromasses of TGF-expanded cells showed loss of aggrecan and type II collagen. Positivity was evidenced for RAGE, IHH, type X collagen and for apoptotic cells, paralleling a reduction of BCL-2 levels, suggesting hypertrophic differentiation. TGF β-1-exposed cells also evidenced increased mRNA levels for bone sialoprotein, osteopontin, matrix metalloproteinase-13, TIMP-3, VEGF and SMAD7, enhanced alkaline phosphatase activity and pyrophosphate availability. Conversely, SMAD3 mRNA and protein contents were reduced. After osteogenic induction, only TGF-expanded cells strongly mineralized and impaired p38 kinase activity, a contributor of chondrocytes' differentiation. To evaluate possible endochondral ossification progression, we seeded the chondrocytes on hydroxyapatite scaffolds, subsequently implanted in an in vivo ectopic setting, but cells failed to reach overt ossification; nonetheless, constructs seeded with TGF-exposed cells displayed blood vessels of the host vascular supply with enlarged diameters, suggestive of vascular remodeling, as in bone growth. Thus TGF-exposure during articular chondrocytes expansion induces a phenotype switch to hypertrophy, an undesirable effect for cells possibly intended for tissue-engineered cartilage repair.

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FAK mediates signal crosstalk between type II collagen and TGF-beta 1 cascades in chondrocytic cells

Cited by 16 publications

References 61 publications

Inhibitors of Src and Focal Adhesion Kinase Promote Endocrine Specification

Inhibitors of Src and Focal Adhesion Kinase Promote Endocrine Specification

An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

TGF β‐1 administration during Ex vivo expansion of human articular chondrocytes in a serum‐free medium redirects the cell phenotype toward hypertrophy

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