The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Mei-ling Ho - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid hormone 1-34 reduces dexamethasone-induced Terminal Differentiation in human articular chondrocytes
Toxicology, 2016Co-Authors: Ling-hua Chang, Shun-cheng Wu, Chung-hwan Chen, Je-ken Chang, Gwo-jaw Wang, Mei-ling HoAbstract:Abstract Intra-articular injection of dexamethasone (Dex) is occasionally used to relieve pain and inflammation in osteoarthritis (OA) patients. Dex induces Terminal Differentiation of chondrogenic mesenchymal stem cells in vitro and causes impaired longitudinal skeletal growth in vivo. Parathyroid hormone 1-34 (PTH 1-34) has been shown to reverse Terminal Differentiation of osteoarthritic articular chondrocytes. We hypothesized that Dex induces Terminal Differentiation of articular chondrocytes and that this effect can be mitigated by PTH 1-34 treatment. We tested the effect of Dex on Terminal Differentiation in human articular chondrocytes and further tested if PTH 1-34 reverses the effects. We found that Dex treatment downregulated chondrogenic-induced expressions of SOX-9 , collagen type IIa1 ( Col2a1 ), and aggrecan and reduced synthesis of cartilaginous matrix (Col2a1 and sulfated glycosaminoglycan) synthesis. Dex treatment upregulated chondrocyte hypertrophic markers of collagen type X and alkaline phosphatase at mRNA and protein levels, and it increased the cell size of articular chondrocytes and induced cell death. These results indicated that Dex induces Terminal Differentiation of articular chondrocytes. To test whether PTH 1-34 treatment reverses Dex-induced Terminal Differentiation of articular chondrocytes, PTH 1-34 was co-administered with Dex. Results showed that PTH 1-34 treatment reversed both changes of chondrogenic and hypertrophic markers in chondrocytes induced by Dex. PTH 1-34 also decreased Dex-induced cell death. PTH 1-34 treatment reduces Dex-induced Terminal Differentiation and apoptosis of articular chondrocytes, and PTH 1-34 treatment may protect articular cartilage from further damage when received Dex administration.
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parathyroid hormone 1 34 inhibits Terminal Differentiation of human articular chondrocytes and osteoarthritis progression in rats
Arthritis & Rheumatism, 2009Co-Authors: Je-ken Chang, Shun-cheng Wu, Shao-hung Hung, Linghwa Chang, Yinchih Fu, Chung-hwan Chen, Gwo-jaw Wang, Mei-ling HoAbstract:Objective Parathyroid hormone 1–34 (PTH[1–34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone–related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1–34) inhibits Terminal Differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA). Methods We studied the effect of PTH(1–34) on human articular chondrocytes with azacytidine (azaC)–induced Terminal Differentiation in vitro and on papain-induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees. Results AzaC induced Terminal Differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3–10 days of treatment with 10 nM PTH(1–34). SOX9 expression was not changed by either azaC or PTH(1–34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of Terminal Differentiation, but PTH(1–34) treatment did not reverse this effect. Furthermore, PTH(1–34) treatment reversed papain-induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats. Conclusion Our findings indicate that PTH(1–34) inhibits the Terminal Differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.
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A novel Terminal Differentiation model of human articular chondrocytes in three-dimensional cultures mimicking chondrocytic changes in osteoarthritis
Cell Biology International, 2006Co-Authors: Mei-ling Ho, Shun-cheng Wu, Ya-hui Chung, Shao-hung Hung, Chung-hwan Chen, Je-ken Chang, Gwo-jaw WangAbstract:This study establishes a cell culture model mimicking the Terminal Differentiation occurring in osteoarthritic chondrocytes. Normal articular chondrocytes obtained from human knees treated with 5-azacytidine (Aza-C) were harvested 3, 7 and 14 days after treatment. Phenotypic and genetic changes of articular chondrocytes were detected. The results show that mRNA expression of collagen type II, a marker for normal functional articular chondrocytes, was significantly decreased after Aza-C treatment in comparison to the control cultures, while those of collagen type X and ALP, markers for hypertrophic chondrocytes, were significantly increased. Cell size and apoptotic rate of articular chondrocytes showed significant increases compared to the control after 14 days of Aza-C treatment. Terminal Differentiation is shown by this model of three-dimensional cultured human articular chondrocytes, which could apply to the studies of the cellular mechanisms of osteoarthritis.
Fiona M Watt - One of the best experts on this subject based on the ideXlab platform.
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PI3-kinase-dependent activation of apoptotic machinery occurs on commitment of epidermal keratinocytes to Terminal Differentiation.
Cell research, 2008Co-Authors: Sam M. Janes, Tyler A. Ofstad, Douglas H. Campbell, Ayad Eddaoudi, Gary Warnes, Derek Davies, Fiona M WattAbstract:We have investigated the earliest events in commitment of human epidermal keratinocytes to Terminal Differentiation. Phosphorylated Akt and caspase activation were detected in cells exiting the basal layer of the epidermis. Activation of Akt by retroviral transduction of primary cultures of human keratinocytes resulted in an increase in abortive clones founded by transit amplifying cells, while inhibition of the upstream kinase, PI3-kinase, inhibited suspension-induced Terminal Differentiation. Caspase inhibition also blocked Differentiation, the primary mediator being caspase 8. Caspase activation was initiated by 2 h in suspension, preceding the onset of expression of the Terminal Differentiation marker involucrin by several hours. Incubation of suspended cells with fibronectin or inhibition of PI3-kinase prevented caspase induction. At 2 h in suspension, keratinocytes that had become committed to Terminal Differentiation had increased side scatter, were 7-aminoactinomycin D (7-AAD) positive and annexin V negative; they exhibited loss of mitochondrial membrane potential and increased cardiolipin oxidation, but with no increase in reactive oxygen species. These properties indicate that the onset of Terminal Differentiation, while regulated by PI3-kinase and caspases, is not a classical apoptotic process.
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Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes Terminal Differentiation: contrasting roles of FOXN1 and Akt
Journal of Cell Science, 2004Co-Authors: Sam M. Janes, Fiona M Watt, Tyler A. Ofstad, Douglas H. Campbell, David M. ProwseAbstract:The forkhead transcription factor FOXN1 is required for normal cutaneous and thymic epithelial development. Mutations in FOXN1 give rise to the nude phenotype in mice, rats and man. However, the genes that are regulated by FOXN1 are unknown. To investigate FOXN1 function we expressed an inducible form of the protein, FOXN1ER, that is activated by 4-hydroxytamoxifen in primary human epidermal keratinocytes. Transient activation of FOXN1 decreased the proportion of keratinocytes that formed actively growing clones attributable to stem cell founders and increased the number of abortive clones, without inducing apoptosis. Within 24 hours the majority of cells had initiated Terminal Differentiation, as assessed by involucrin expression. We performed a cDNA microarray experiment to analyse changes in the transcription of approximately 6000 genes. Following FOXN1 activation we detected increases of two fold or greater in the RNA levels of over 30 genes. Genes promoting growth arrest, survival and Differentiation featured prominently and markers of early events in keratinocyte Differentiation were also detected. Since one of the induced genes was Akt we investigated whether Akt played a role in Terminal Differentiation. Activation of PI 3-kinase but not Akt was necessary for FOXN1-induced Differentiation. In reconstituted epidermis FOXN1 promoted early stages of Terminal Differentiation whereas Akt activation was sufficient to induce late stages, including formation of the cornified layers. These results establish a role for FOXN1 in initiation of Terminal Differentiation and implicate Akt in subsequent events.
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Evidence that apoptosis and Terminal Differentiation of epidermal keratinocytes are distinct processes.
Experimental dermatology, 1999Co-Authors: A. Gandarillas, Lowell A. Goldsmith, S. Gschmeissner, Irene M. Leigh, Fiona M WattAbstract:Although there are clear parallels between apoptosis and epidermal Terminal Differentiation it is unclear whether Terminal Differentiation of keratinocytes is a form of apoptosis. We found that apoptosis was rare in adherent cultures of normal keratinocytes, even when growth factors were removed. When keratinocytes were placed in suspension for 24-96 h the majority of cells were induced to undergo Terminal Differentiation, as assessed by involucrin expression and cornified envelope assembly, but few cells underwent apoptosis, as assessed by morphological examination, TUNEL labelling and by DNA laddering. Withdrawal of serum and growth factors stimulated apoptosis of suspended keratinocytes but led to some reduction in the number of cells that underwent Terminal Differentiation. At 96 h the majority of cells retained their nuclei in the presence or absence of serum and growth factors. In normal epidermis only occasional cells within the granular layer had apoptotic nuclei, determined by TUNEL labelling and light and electron microscopy. In affected epidermis of psoriasis, Darier's disease and pityriasis rubra pilaris, diseases characterized by perturbation of growth, Differentiation or adhesion, light microscopy revealed no higher proportion of apoptotic nuclei than in normal epidermis. However, the majority of viable epidermal layers in diseased skin were positive by TUNEL labelling, suggesting that TUNEL is not always a specific marker of apoptosis in keratinocytes. We conclude that in vivo and in culture keratinocyte Terminal Differentiation and apoptosis are distinct cellular events, subject to different stimuli.
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Regulation of cell surface beta 1 integrin levels during keratinocyte Terminal Differentiation.
The Journal of cell biology, 1995Co-Authors: Neil A. Hotchin, A. Gandarillas, Fiona M WattAbstract:Integrins of the beta 1 family play a central role in controlling adhesion and Terminal Differentiation within the epidermis. When human epidermal keratinocytes undergo Terminal Differentiation, intracellular transport of newly synthesized integrins is inhibited, and mature receptors are lost from the cell surface. We have examined the mechanisms underlying these processes, using an experimental model in which keratinocytes are placed in suspension to induce Terminal Differentiation. The block in intracellular transport was keratinocyte- and integrin-specific since it was not observed when fibroblasts were placed in suspension and did not affect E-cadherin synthesis in suspended keratinocytes. Newly synthesized beta 1 integrins associated with an endoplasmic reticulum resident protein, calnexin; the association was prolonged when keratinocytes were placed in suspension, suggesting a role for calnexin in the inhibition of transport. After 24 h, the level of beta 1 integrin mRNA declines in suspended keratinocytes, reflecting inhibition of gene transcription, but in fibroblasts, the level remained constant. Transport of integrins could be blocked in both adherent keratinocytes and fibroblasts by inhibiting total protein synthesis, raising the possibility that transport is coupled to de novo integrin synthesis. The fate of receptors on the surface of keratinocytes was followed by confocal immunofluorescence microscopy, immunoelectron microscopy, and biochemical analysis: with the onset of Terminal Differentiation, endocytosed receptors were transported to the lysosomes. These experiments reveal novel mechanisms by which integrin levels can be controlled. Together with our earlier evidence for transcriptional regulation and affinity modulation of integrins, they highlight the complexity of the mechanisms which ensure that the onset of Terminal Differentiation is linked to detachment of keratinocytes from the underlying basement membrane.
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Evidence that cadherins play a role in the downregulation of integrin expression that occurs during keratinocyte Terminal Differentiation.
The Journal of cell biology, 1994Co-Authors: K. J. Hodivala, Fiona M WattAbstract:In epidermis the onset of Terminal Differentiation normally coincides with inhibition of integrin function and expression, thereby ensuring that differentiating cells are selectively expelled from the basal layer. However, when stratification of cultured human epidermal keratinocytes is prevented by reducing the calcium concentration of the medium to 0.1 mM, keratinocytes initiate Terminal Differentiation while still attached to the culture substrate. We have examined the mechanism by which differentiating keratinocytes adhere to extracellular matrix proteins in low calcium medium and the consequences of inducing stratification by raising the calcium ion concentration to 1.8 mM (Standard Medium). In low calcium medium keratinocytes co-expressed integrins and Terminal Differentiation markers such as involucrin and peanut lectin-binding glycoproteins: differentiating cells contained integrin mRNA, synthesized integrin proteins de novo and expressed functional mature integrins. There were no differences in integrin synthesis, maturation or break down in low calcium or standard medium, although the level of beta 1 integrins on the surface of proliferating cells was higher in standard medium. Within 6 h of transfer from low calcium to standard medium integrin mRNA was no longer detectable in Terminally differentiating cells, integrins were being lost from the cell surface, and selective migration out of the basal layer had begun. Antibodies to P- and E-cadherin, which block calcium-induced stratification, prevented the selective loss of integrin mRNA and protein from Terminally differentiating cells. This suggests that cadherins may play a role in the down-regulation of integrin expression that is associated with Terminal Differentiation.
Je-ken Chang - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid hormone 1-34 reduces dexamethasone-induced Terminal Differentiation in human articular chondrocytes
Toxicology, 2016Co-Authors: Ling-hua Chang, Shun-cheng Wu, Chung-hwan Chen, Je-ken Chang, Gwo-jaw Wang, Mei-ling HoAbstract:Abstract Intra-articular injection of dexamethasone (Dex) is occasionally used to relieve pain and inflammation in osteoarthritis (OA) patients. Dex induces Terminal Differentiation of chondrogenic mesenchymal stem cells in vitro and causes impaired longitudinal skeletal growth in vivo. Parathyroid hormone 1-34 (PTH 1-34) has been shown to reverse Terminal Differentiation of osteoarthritic articular chondrocytes. We hypothesized that Dex induces Terminal Differentiation of articular chondrocytes and that this effect can be mitigated by PTH 1-34 treatment. We tested the effect of Dex on Terminal Differentiation in human articular chondrocytes and further tested if PTH 1-34 reverses the effects. We found that Dex treatment downregulated chondrogenic-induced expressions of SOX-9 , collagen type IIa1 ( Col2a1 ), and aggrecan and reduced synthesis of cartilaginous matrix (Col2a1 and sulfated glycosaminoglycan) synthesis. Dex treatment upregulated chondrocyte hypertrophic markers of collagen type X and alkaline phosphatase at mRNA and protein levels, and it increased the cell size of articular chondrocytes and induced cell death. These results indicated that Dex induces Terminal Differentiation of articular chondrocytes. To test whether PTH 1-34 treatment reverses Dex-induced Terminal Differentiation of articular chondrocytes, PTH 1-34 was co-administered with Dex. Results showed that PTH 1-34 treatment reversed both changes of chondrogenic and hypertrophic markers in chondrocytes induced by Dex. PTH 1-34 also decreased Dex-induced cell death. PTH 1-34 treatment reduces Dex-induced Terminal Differentiation and apoptosis of articular chondrocytes, and PTH 1-34 treatment may protect articular cartilage from further damage when received Dex administration.
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parathyroid hormone 1 34 inhibits Terminal Differentiation of human articular chondrocytes and osteoarthritis progression in rats
Arthritis & Rheumatism, 2009Co-Authors: Je-ken Chang, Shun-cheng Wu, Shao-hung Hung, Linghwa Chang, Yinchih Fu, Chung-hwan Chen, Gwo-jaw Wang, Mei-ling HoAbstract:Objective Parathyroid hormone 1–34 (PTH[1–34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone–related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1–34) inhibits Terminal Differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA). Methods We studied the effect of PTH(1–34) on human articular chondrocytes with azacytidine (azaC)–induced Terminal Differentiation in vitro and on papain-induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees. Results AzaC induced Terminal Differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3–10 days of treatment with 10 nM PTH(1–34). SOX9 expression was not changed by either azaC or PTH(1–34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of Terminal Differentiation, but PTH(1–34) treatment did not reverse this effect. Furthermore, PTH(1–34) treatment reversed papain-induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats. Conclusion Our findings indicate that PTH(1–34) inhibits the Terminal Differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.
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A novel Terminal Differentiation model of human articular chondrocytes in three-dimensional cultures mimicking chondrocytic changes in osteoarthritis
Cell Biology International, 2006Co-Authors: Mei-ling Ho, Shun-cheng Wu, Ya-hui Chung, Shao-hung Hung, Chung-hwan Chen, Je-ken Chang, Gwo-jaw WangAbstract:This study establishes a cell culture model mimicking the Terminal Differentiation occurring in osteoarthritic chondrocytes. Normal articular chondrocytes obtained from human knees treated with 5-azacytidine (Aza-C) were harvested 3, 7 and 14 days after treatment. Phenotypic and genetic changes of articular chondrocytes were detected. The results show that mRNA expression of collagen type II, a marker for normal functional articular chondrocytes, was significantly decreased after Aza-C treatment in comparison to the control cultures, while those of collagen type X and ALP, markers for hypertrophic chondrocytes, were significantly increased. Cell size and apoptotic rate of articular chondrocytes showed significant increases compared to the control after 14 days of Aza-C treatment. Terminal Differentiation is shown by this model of three-dimensional cultured human articular chondrocytes, which could apply to the studies of the cellular mechanisms of osteoarthritis.
Gwo-jaw Wang - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid hormone 1-34 reduces dexamethasone-induced Terminal Differentiation in human articular chondrocytes
Toxicology, 2016Co-Authors: Ling-hua Chang, Shun-cheng Wu, Chung-hwan Chen, Je-ken Chang, Gwo-jaw Wang, Mei-ling HoAbstract:Abstract Intra-articular injection of dexamethasone (Dex) is occasionally used to relieve pain and inflammation in osteoarthritis (OA) patients. Dex induces Terminal Differentiation of chondrogenic mesenchymal stem cells in vitro and causes impaired longitudinal skeletal growth in vivo. Parathyroid hormone 1-34 (PTH 1-34) has been shown to reverse Terminal Differentiation of osteoarthritic articular chondrocytes. We hypothesized that Dex induces Terminal Differentiation of articular chondrocytes and that this effect can be mitigated by PTH 1-34 treatment. We tested the effect of Dex on Terminal Differentiation in human articular chondrocytes and further tested if PTH 1-34 reverses the effects. We found that Dex treatment downregulated chondrogenic-induced expressions of SOX-9 , collagen type IIa1 ( Col2a1 ), and aggrecan and reduced synthesis of cartilaginous matrix (Col2a1 and sulfated glycosaminoglycan) synthesis. Dex treatment upregulated chondrocyte hypertrophic markers of collagen type X and alkaline phosphatase at mRNA and protein levels, and it increased the cell size of articular chondrocytes and induced cell death. These results indicated that Dex induces Terminal Differentiation of articular chondrocytes. To test whether PTH 1-34 treatment reverses Dex-induced Terminal Differentiation of articular chondrocytes, PTH 1-34 was co-administered with Dex. Results showed that PTH 1-34 treatment reversed both changes of chondrogenic and hypertrophic markers in chondrocytes induced by Dex. PTH 1-34 also decreased Dex-induced cell death. PTH 1-34 treatment reduces Dex-induced Terminal Differentiation and apoptosis of articular chondrocytes, and PTH 1-34 treatment may protect articular cartilage from further damage when received Dex administration.
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parathyroid hormone 1 34 inhibits Terminal Differentiation of human articular chondrocytes and osteoarthritis progression in rats
Arthritis & Rheumatism, 2009Co-Authors: Je-ken Chang, Shun-cheng Wu, Shao-hung Hung, Linghwa Chang, Yinchih Fu, Chung-hwan Chen, Gwo-jaw Wang, Mei-ling HoAbstract:Objective Parathyroid hormone 1–34 (PTH[1–34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone–related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1–34) inhibits Terminal Differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA). Methods We studied the effect of PTH(1–34) on human articular chondrocytes with azacytidine (azaC)–induced Terminal Differentiation in vitro and on papain-induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees. Results AzaC induced Terminal Differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3–10 days of treatment with 10 nM PTH(1–34). SOX9 expression was not changed by either azaC or PTH(1–34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of Terminal Differentiation, but PTH(1–34) treatment did not reverse this effect. Furthermore, PTH(1–34) treatment reversed papain-induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats. Conclusion Our findings indicate that PTH(1–34) inhibits the Terminal Differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.
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A novel Terminal Differentiation model of human articular chondrocytes in three-dimensional cultures mimicking chondrocytic changes in osteoarthritis
Cell Biology International, 2006Co-Authors: Mei-ling Ho, Shun-cheng Wu, Ya-hui Chung, Shao-hung Hung, Chung-hwan Chen, Je-ken Chang, Gwo-jaw WangAbstract:This study establishes a cell culture model mimicking the Terminal Differentiation occurring in osteoarthritic chondrocytes. Normal articular chondrocytes obtained from human knees treated with 5-azacytidine (Aza-C) were harvested 3, 7 and 14 days after treatment. Phenotypic and genetic changes of articular chondrocytes were detected. The results show that mRNA expression of collagen type II, a marker for normal functional articular chondrocytes, was significantly decreased after Aza-C treatment in comparison to the control cultures, while those of collagen type X and ALP, markers for hypertrophic chondrocytes, were significantly increased. Cell size and apoptotic rate of articular chondrocytes showed significant increases compared to the control after 14 days of Aza-C treatment. Terminal Differentiation is shown by this model of three-dimensional cultured human articular chondrocytes, which could apply to the studies of the cellular mechanisms of osteoarthritis.
Christophe Sirac - One of the best experts on this subject based on the ideXlab platform.
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B-cell receptor signal strength influences Terminal Differentiation.
European journal of immunology, 2013Co-Authors: Fabien Lechouane, Amélie Bonaud, Laurent Delpy, Stefano Casola, Zéliha Oruc, Guillaume Chemin, Michel Cogné, Christophe SiracAbstract:B-cell Terminal Differentiation into antibody secreting plasma cells (PCs) features a transcriptional shift driven by the activation of plasma cell lineage determinants such as Blimp-1 and Xbp-1, together with the extinction of Pax5. Little is known about the signals inducing this change in transcriptional networks and the role of the B-cell receptor (BCR) in Terminal Differentiation remains especially controversial. Here, we show that tonic BCR signal strength influences PC commitment in vivo. Using immuno-globulin light chain transgenic mice expressing suboptimal surface BCR levels and latent membrane protein 2A knock-in animals with defined BCR-like signal strengths, we show that weak, antigen-independent constitutive BCR signaling facilitates spontaneous PC Differentiation in vivo and in vitro in response to TLR agonists or CD40/IL-4. Conversely, increasing tonic signaling completely prevents this process that is rescued by lowering surface BCR expression or through the inhibition of Syk phosphorylation. These findings provide new insights into the role of basal BCR signaling in PC Differentiation and point to the need to resolve a strong BCR signal in order to guarantee Terminal Differentiation.
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B-cell receptor signal strength influences Terminal Differentiation.
European Journal of Immunology, 2012Co-Authors: Fabien Lechouane, Amélie Bonaud, Laurent Delpy, Stefano Casola, Zéliha Oruc, Guillaume Chemin, Michel Cogné, Christophe SiracAbstract:B-cell Terminal Differentiation into antibody secreting plasma cells (PCs) features a transcriptional shift driven by the activation of plasma cell lineage determinants such as Blimp-1 and Xbp-1, together with the extinction of Pax5. Little is known about the signals inducing this change in transcriptional networks and the role of the B-cell receptor (BCR) in Terminal Differentiation remains especially controversial. Here, we show that tonic BCR signal strength influences PC commitment in vivo. Using immunoglobulin light chain transgenic mice expressing suboptimal surface BCR levels and LMP2A knock-in animals with defined BCR-like signal strengths, we show that weak, antigen-independent constitutive BCR signaling facilitates spontaneous PC Differentiation in vivo and in vitro in response to TLR agonists or CD40/IL4. Conversely, increasing tonic signaling completely prevents this process which is rescued by lowering surface BCR expression or through the inhibition of Syk phosphorylation. These findings provide new insights into the role of basal BCR signaling in PC Differentiation and point to the need to resolve a strong BCR signal in order to guarantee Terminal Differentiation.