Age-related decrease in the responsiveness of rat articular chondrocytes to EGF is associated with diminished number and affinity for the ligand of cell surface binding sites

Ribault, Didier; Messai, Habib; Khatib, Abdel‐Majid; Barbara, A.; Mitrović, D

doi:10.1016/s0047-6374(97)00115-2

Cited by 33 publications

(12 citation statements)

References 39 publications

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“…Some possibilities include an age-dependence in the response to exogenous factors present in the culture medium, in the expression levels of endogenous factors from donor chondrocytes [17], and in the synthesis and accumulation of ECM molecules [18][19][20]. Chondrocytes from aged animals (5-7 years old) produced very small and ECM-poor outgrowths, reflecting low levels of proliferation and reduced ECM synthesis that agree with previous in vitro findings [6,19,[21][22][23][24][25].…”

Section: Discussionsupporting

confidence: 83%

Young Adult Chondrocytes Proliferate Rapidly and Produce a Cartilaginous Tissue at the Gel-Media Interface in Agarose Cultures

Tran-Khanh

Chevrier

Lascau-Coman

et al. 2010

Connective Tissue Research

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Primary chondrocytes cultured in agarose can escape the gel, accumulate at the interface between agarose and the culture medium, and form an outgrowing tissue. These outgrowths can appear as voluminous cartilage-like nodules that have never been previously investigated. In the present study, bovine articular chondrocytes from three age groups (fetal, young adult, aged) were seeded and cultured in agarose to test the hypothesis that hyaline-like cartilage outgrowths develop at the interface by appositional growth, in an age-dependant manner. Macroscopic appearance, cell content, cell division, cytoskeletal morphology, and extracellular matrix (ECM) composition were analyzed. Fetal chondrocytes produced a fibrous interfacial tissue while aged chondrocytes produced ECM-poor cell clusters. In contrast young adult chondrocytes produced large cartilaginous outgrowths, rich in proteoglycan and collagen II, where cells in the central region displayed a chondrocyte morphology. Cell proliferation was confined to the peripheral edge of these outgrowths, where elongated cell morphology, cell-cell contacts, and cell extensions toward the culture medium were seen. Thus these voluminous cartilaginous outgrowths formed in an appositional growth process and only for donor chondrocytes from young adult animals. This system offers an interesting ability to proliferate chondrocytes in a manner that results in a chondrocyte morphology and a cartilaginous ECM in central regions of the outgrowing tissue. It also provides an in vitro model system to study neocartilage appositional growth.

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Section: Discussionsupporting

confidence: 83%

Young Adult Chondrocytes Proliferate Rapidly and Produce a Cartilaginous Tissue at the Gel-Media Interface in Agarose Cultures

Tran-Khanh

Chevrier

Lascau-Coman

et al. 2010

Connective Tissue Research

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“…) is altered [33][34][35]. In OA cartilage, expression of β-galactosidase was increased close to but not away from the OA damage sites suggesting that cell senescence plays a role in the progression of aging cartilage towards disease [36].…”

Section: αmentioning

confidence: 99%

Cartilage tissue engineering for degenerative joint disease☆

Nešić

Whiteside

Brittberg

et al. 2006

Advanced Drug Delivery Reviews

210

156

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Pain in the joint is often due to cartilage degeneration and represents a serious medical problem affecting people of all ages. Although many, mostly surgical techniques, are currently employed to treat cartilage lesions, none has given satisfactory results in the long term. Recent advances in biology and material science have brought tissue engineering to the forefront of new cartilage repair techniques. The combination of autologous cells, specifically designed scaffolds, bioreactors, mechanical stimulations and growth factors together with the knowledge that underlies the principles of cell biology offers promising avenues for cartilage tissue regeneration. The present review explores basic biology mechanisms for cartilage reconstruction and summarizes the advances in the tissue engineering approaches. Furthermore, the limits of the new methods and their potential application in the osteoarthritic conditions are discussed.

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“…In aged human diploid fibroblasts, the decreased response to growth factors is suggested to be associated with a repression of c-fos expression, a reduced AP-1 DNA binding, and diminished DNA synthesis. Senescent cells in culture or tissues have been reported to have normal numbers of EGF 1 receptors (EGFRs) (5,6), and the binding capacity of EGF to EGFR is normal (7). However, there is no mitogenactivated protein kinase activation upon EGF stimulation in senescent cells, and the mechanism for the age-related modulation of EGFR in response to the EGF stimulation is not yet fully resolved.…”

mentioning

confidence: 99%

Up-regulation of Caveolin Attenuates Epidermal Growth Factor Signaling in Senescent Cells

Park

Cho

et al. 2000

Journal of Biological Chemistry

209

182

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Senescent human diploid fibroblasts do not respond to growth factors like epidermal growth factor (EGF), although they have a normal level of receptors and downstream signaling molecules. To examine the mechanism of signaling attenuation, we investigated Erk activation after EGF stimulation in senescent cells. Senescent cells did not phosphorylate Erk-1/2 after EGF stimulation, whereas young cells did. In those senescent cells, we found an increased level of caveolin proteins and strong interactions between caveolin-1 and EGF receptor. Electron microscopic analysis demonstrated an increased number of caveolae structures in senescent cells. More interestingly, brain, spleen, and lung from 26-month-old rats showed substantial increases of caveolin proteins. However, in the case of p53-induced senescence, caveolin-1 was not induced, and EGF stimulation phosphorylated Erk-1/2 as much as young control cells. Finally, we overexpressed caveolin-1 in young human diploid fibroblasts in which the activation of Erk-1/2 upon EGF stimulation was significantly suppressed. These results suggest that the unresponsiveness of senescent fibroblasts to EGF stimulation may be due to the overexpression of caveolins, which seems to be independent of growth arrest and other aging phenotypes.Normal human diploid cells show cellular senescence in vitro after a finite number of population doublings (1). Although senescent cells can maintain their metabolic activity, the loss of proliferation capacity may be due to a diminished response to growth factors (2-4). In aged human diploid fibroblasts, the decreased response to growth factors is suggested to be associated with a repression of c-fos expression, a reduced AP-1 DNA binding, and diminished DNA synthesis. Senescent cells in culture or tissues have been reported to have normal numbers of EGF 1 receptors (EGFRs) (5, 6), and the binding capacity of EGF to EGFR is normal (7). However, there is no mitogenactivated protein kinase activation upon EGF stimulation in senescent cells, and the mechanism for the age-related modulation of EGFR in response to the EGF stimulation is not yet fully resolved. Caveolae are vesicular invaginations of the plasma membrane with a diameter of 50 -100 nm (8, 9) and regulate signal transduction, potocytosis, and transcytosis (10, 11). Caveolin, a 21-24-kDa integral membrane protein, is a principal structural component of caveolae membranes in vivo. The stable expression of the caveolin-1 or -3 gene to the mammalian cells without caveolin induced the formation of caveolae structures (12). Caveolin functions as a scaffolding protein within the caveolae membrane and interacts with signaling proteins, namely EGFR, G-proteins, Src-like kinases, Ha-Ras, protein kinase C, endothelial nitric-oxide synthase, integrin and so on (13-18). A short cytosolic N-terminal region of caveolin is involved in the formation of oligomers and mediates the interaction with these signal molecules, which results in the inactivation of signaling (11). The suppression of these signaling m...

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Age-related decrease in the responsiveness of rat articular chondrocytes to EGF is associated with diminished number and affinity for the ligand of cell surface binding sites

Cited by 33 publications

References 39 publications

Young Adult Chondrocytes Proliferate Rapidly and Produce a Cartilaginous Tissue at the Gel-Media Interface in Agarose Cultures

Young Adult Chondrocytes Proliferate Rapidly and Produce a Cartilaginous Tissue at the Gel-Media Interface in Agarose Cultures

Cartilage tissue engineering for degenerative joint disease☆

Up-regulation of Caveolin Attenuates Epidermal Growth Factor Signaling in Senescent Cells

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