Role of polyamines in hypertrophy and terminal differentiation of osteoarthritic chondrocytes

Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy “maturation arrested state” and resume their natural route of proliferation, hypertrophy, and terminal differentiation. The latter are hallmarks of OA that are easily evaluated in vitro in 2-D or 3-D culture models. The aim of our study was to investigate the effect of NOTCH1 knockdown on proliferation (cell count and Picogreen mediated DNA quantification), cell cycle (flow cytometry), hypertrophy (gene and protein expression of key markers such as RUNX2 and MMP-13), and terminal differentiation (viability measured in 3-D cultures by luminescence assay) of human OA chondrocytes. NOTCH1 silencing of OA chondrocytes yielded a healthier phenotype in both 2-D (reduced proliferation) and 3-D with evidence of decreased hypertrophy (reduced expression of RUNX2 and MMP-13) and terminal differentiation (increased viability). This demonstrates that NOTCH1 is a convenient therapeutic target to attenuate OA progression.

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Interleukin-6 and the Granulocyte Colony-Stimulating Factor Receptor Are Major Independent Regulators of Granulopoiesis In Vivo But Are Not Required for Lineage Commitment or Terminal Differentiation

Blood ◽

10.1182/blood.v90.7.2583.2583_2583_2590 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2583-2590 ◽

Cited By ~ 8

Author(s):

Fulu Liu ◽

Jennifer Poursine-Laurent ◽

Huai Yang Wu ◽

Daniel C. Link

Keyword(s):

Interleukin 6 ◽

Terminal Differentiation ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Normal Numbers ◽

Stimulating Factor ◽

Deficient Mice ◽

Additional Loss

Multiple hematopoietic cytokines can stimulate granulopoiesis; however, their relative importance in vivo and mechanisms of action remain unclear. We recently reported that granulocyte colony-stimulating factor receptor (G-CSFR)-deficient mice have a severe quantitative defect in granulopoiesis despite which phenotypically normal neutrophils were still detected. These results confirmed a role for the G-CSFR as a major regulator of granulopoiesis in vivo, but also indicated that G-CSFR independent mechanisms of granulopoiesis must exist. To explore the role of interleukin-6 (IL-6) in granulopoiesis, we generated IL-6 × G-CSFR doubly deficient mice. The additional loss of IL-6 significantly worsened the neutropenia present in young adult G-CSFR–deficient mice; moreover, exogenous IL-6 stimulated granulopoiesis in vivo in the absence of G-CSFR signals. Near normal numbers of myeloid progenitors were detected in the bone marrow of IL-6 × G-CSFR–deficient mice and their ability to terminally differentiate into mature neutrophils was observed. These results indicate that IL-6 is an independent regulator of granulopoiesis in vivo and show that neither G-CSFR or IL-6 signals are required for the commitment of multipotential progenitors to the myeloid lineage or for their terminal differentiation.

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The Critical Role of 15-Lipoxygenase-1 in Colorectal Epithelial Cell Terminal Differentiation and Tumorigenesis

Cancer Research ◽

10.1158/0008-5472.can-05-2180 ◽

2005 ◽

Vol 65 (24) ◽

pp. 11486-11492 ◽

Cited By ~ 65

Author(s):

Imad Shureiqi ◽

Yuanqing Wu ◽

Dongning Chen ◽

Xiu L. Yang ◽

Baoxiang Guan ◽

...

Keyword(s):

Epithelial Cell ◽

Critical Role ◽

Terminal Differentiation

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Role of 1,25-dihydroxycholecalciferol in growth-plate cartilage: inhibition of terminal differentiation of chondrocytes in vitro and in vivo.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.87.17.6522 ◽

1990 ◽

Vol 87 (17) ◽

pp. 6522-6526 ◽

Cited By ~ 35

Author(s):

Y. Kato ◽

A. Shimazu ◽

M. Iwamoto ◽

K. Nakashima ◽

T. Koike ◽

...

Keyword(s):

Growth Plate ◽

Terminal Differentiation ◽

Growth Plate Cartilage

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4-Hydroxynonenal induces apoptosis in human osteoarthritic chondrocytes: the protective role of glutathione-S-transferase

Arthritis Research & Therapy ◽

10.1186/ar2503 ◽

2008 ◽

Vol 10 (5) ◽

pp. R107 ◽

Cited By ~ 60

Author(s):

France Vaillancourt ◽

Hassan Fahmi ◽

Qin Shi ◽

Patrick Lavigne ◽

Pierre Ranger ◽

...

Keyword(s):

Protective Role ◽

Glutathione S Transferase ◽

Osteoarthritic Chondrocytes

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Prostacyclin as a potent effector of adipose-cell differentiation

Biochemical Journal ◽

10.1042/bj2570399 ◽

1989 ◽

Vol 257 (2) ◽

pp. 399-405 ◽

Cited By ~ 101

Author(s):

R Négrel ◽

D Gaillard ◽

G Ailhaud

Keyword(s):

Arachidonic Acid ◽

Cyclic Amp ◽

Critical Role ◽

Terminal Differentiation ◽

Prostaglandin F2 Alpha ◽

Adipogenic Effect ◽

Adipose Cells

The terminal differentiation of Ob1771 pre-adipose cells induced by arachidonic acid in serum-free hormone-supplemented medium containing insulin, transferrin, growth hormone, tri-iodothyronine and fetuin (5F medium) was strongly diminished in the presence of inhibitors of prostaglandin synthesis, namely aspirin or indomethacin. Carbaprostacyclin, a stable analogue of prostacyclin (prostaglandin I2) known to be synthesized by pre-adipocytes and adipocytes, behaved as an efficient activator of cyclic AMP production and was able, when added to 5F medium, to mimic the adipogenic effect of arachidonic acid. Prostaglandins E2, F2 alpha and D2, unable to affect the cyclic AMP production, failed to substitute for carbaprostacyclin. However, prostaglandin F2 alpha, which is another metabolite of arachidonic acid in pre-adipose and adipose cells, able to promote inositol phospholipid breakdown and protein kinase C activation, potentiated the adipogenic effect of carbaprostacyclin. In addition, carbaprostacyclin enhanced both a limited proliferation and terminal differentiation of adipose precursor cells isolated from rodent and human adipose tissues maintained in primary culture. These results demonstrate the critical role of prostacyclin and prostaglandin F2 alpha on adipose conversion in vitro and suggest a paracrine/autocrine role of both prostanoids in the development of adipose tissue in vivo.

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Bcl2 inhibits apoptosis associated with terminal differentiation of HL- 60 myeloid leukemia cells

Blood ◽

10.1182/blood.v83.8.2261.2261 ◽

1994 ◽

Vol 83 (8) ◽

pp. 2261-2267 ◽

Cited By ~ 87

Author(s):

L Naumovski ◽

ML Cleary

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Myeloid Cells ◽

Terminal Differentiation ◽

Retroviral Gene Transfer ◽

Protein Levels ◽

All Trans Retinoic Acid ◽

Bcl2 Protein ◽

The Relationship

Abstract The Bcl2 protein inhibits apoptosis (programmed cell death) induced by a variety of noxious stimuli. However, relatively little is known about its effect on apoptosis that occurs after terminal differentiation. Bcl2 protein levels decrease during differentiation of myeloid cells into granulocytes that subsequently undergo apoptosis, but the potential role of Bcl2 in coupling survival and differentiation remains undefined. To ascertain the relationship between decreasing Bcl2 levels and the onset of apoptosis in differentiating myeloid cells, Bcl2 was hyperexpressed in the HL-60 cell line after retroviral gene transfer. After treatment of HL-60/BCL2 cells with all-trans retinoic acid or phorbol myristic acid, Bcl2 levels did not decrease as in normal HL-60 cells but, rather, increased because of activation of the viral promoter. Differentiation of the Bcl2-overexpressing cells was similar to that of normal HL-60 cells, but they showed little evidence for apoptosis and had a prolonged survival. These studies show that the survival-enhancing properties of Bcl2 counteract programmed cell death that accompanies terminal differentiation; however, Bcl2 has no significant effect on differentiation itself, suggesting that apoptosis and differentiation are regulated independently in myeloid cells.

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