Hypoxia-induced hyaluronan synthesis by articular chondrocytes: the role of nitric oxide

Hashimoto, Kazuhiko; Fukuda, Kanji; Yamazaki, Kenji; Yamamoto, N.; Matsushita, Takehiko; Hayakawa, Sumio; Munakata, Hiroshi; Hamanishi, Chiaki

doi:10.1007/s00011-005-0012-6

Cited by 29 publications

(23 citation statements)

References 35 publications

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“…To validate our culture system, we first confirmed the expression of accepted marker genes that have been shown to be hypoxia-responsive in different species and in vitro settings (Fujita et al, 2012;Hashimoto et al, 2006;Lafont et al, 2008;Lee et al, 2010). We, therefore, used these genes as robust indicators of cellular hypoxia on mRNA level: a highly significant upregulation was found for four out of five of these markers under 1% pO 2 (Fig.…”

Section: Hypoxia and Chondrocyte Marker Expressionmentioning

confidence: 59%

“…We confirmed its strong, 20-fold, induction in hypoxic chondrocytes. Others reported VEGF, GDF10, HAS2 and COX-2 (PTGS2) as hypoxia responsive genes (Fujita et al, 2012;Hashimoto et al, 2006;Lafont et al, 2008;Lee et al, 2010;Marxsen et al, 2001). Expression of vascular endothelial growth factor, VEGF, is hypoxiainducible in cartilage cells (Zhang et al, 2012), but the magnitude of its induction (20-fold, Fig.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

TGF-β2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions

Das

Timur

Edip

et al. 2015

Annals of Anatomy - Anatomischer Anzeiger

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Section: Hypoxia and Chondrocyte Marker Expressionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 94%

TGF-β2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions

Das

Timur

Edip

et al. 2015

Annals of Anatomy - Anatomischer Anzeiger

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“…NO production in response to mechanical compression is significantly reduced at 1% O 2 compared with 20% O 2 , but is similar at 5% and 20% O 2 . Cartilage cultured at 5% O 2 (with no mechanical compression) has an increased level of baseline NO production Hashimoto et al, 2006), compared with 20% or 1% O 2 , and this stimulation is not further affected by mechanical compression. Therefore both the baseline and mechanically induced production of NO is dependent on the oxygen tension of the culture environment.…”

Section: Effects Of Oxygen On Mechanically Induced No Productionmentioning

confidence: 99%

Oxygen, nitric oxide and articular cartilage

Fermor

Christensen²,

Youn³

et al. 2007

eCM

124

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Molecular oxygen is required for the production of nitric oxide (NO), a pro-inflammatory mediator that is associated with osteoarthritis and rheumatoid arthritis. To date there has been little consideration of the role of oxygen tension in the regulation of nitric oxide production associated with arthritis. Oxygen tension may be particularly relevant to articular cartilage since it is avascular and therefore exists at a reduced oxygen tension. The superficial zone exists at approximately 6% O 2 , while the deep zone exists at less than 1% O 2 . Furthermore, oxygen tension can alter matrix synthesis, and the material properties of articular cartilage in vitro.The increase in nitric oxide associated with arthritis can be caused by pro-inflammatory cytokines and mechanical stress. Oxygen tension significantly alters endogenous NO production in articular cartilage, as well as the stimulation of NO in response to both mechanical loading and proinflammatory cytokines. Mechanical loading and proinflammatory cytokines also increase the production of prostaglandin E2 (PGE 2 ). There is a complex interaction between NO and PGE 2 , and oxygen tension can alter this interaction. These findings suggest that the relatively low levels of oxygen within the joint may have significant influences on the metabolic activity, and inflammatory response of cartilage as compared to ambient levels. A better understanding of the role of oxygen in the production of inflammatory mediators in response to mechanical loading, or pro-inflammatory cytokines, may aid in the development of strategies for therapeutic intervention in arthritis.

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“…12 The presence of a tonic activation of HIF-1a (hypoxia inducible factor 1 alpha) within the chondrocytes 13,14 strongly supports the assumption of a hypoxic environment. Ex vivo, chondrocyte-specific gene expression 15 and protein, 16,17 as well as glycosaminoglycan secretion, 18 was maintained in a HIF1a-dependent manner 16,19 by culturing primary chondrocytes in low oxygen concentrations. Furthermore, the adaptation of chondrocytes to anaerobic energy generation in vivo was maintained in vitro by applying hypoxic conditions.…”

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confidence: 99%

Hypoxic expansion promotes the chondrogenic potential of articular chondrocytes

Egli

Bastian

Ganz

et al. 2008

Journal Orthopaedic Research

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For cell-based cartilage repair strategies, an ex vivo expansion phase is required to obtain sufficient numbers of cells needed for therapy. Although recent reports demonstrated the central role of oxygen for the function and differentiation of chondrocytes, a beneficial effect of low oxygen concentrations during the expansion of the cells to further improve their chondrogenic capacity has not been investigated. Therefore, freshly harvested bovine articular chondrocytes were grown in two-dimensional monolayer cultures at 1.5% and 21% O 2 and redifferentiation was subsequently induced in three-dimensional micromass cultures at 1.5%, 5%, and 21% O 2 . Cells expanded at 1.5% O 2 were characterized by low citrate synthase (aerobic energy metabolism)-and high LDH (anaerobic energy metabolism)-activities, suggesting an anaerobic energy metabolism. Collagen type II mRNA was twofold higher in cells expanded at 1.5% as compared to expansion at 21% O 2 . Micromass cultures grown at 21% O 2 showed up to a twofold increase in the tissue content of glycosaminoglycans when formed with cells expanded at 1.5% instead of 21% O 2 . However, no differences in the levels of transcripts and in the staining for collagen type II protein were observed in these micromass cultures. Hypoxia (1.5% and 5% O 2 ) applied during micromass cultures gave rise to tissues with low contents of glycosaminoglycans only. In vivo, the chondrocytes are adapted to a hypoxic environment. Taking this into account, by applying 1.5% O 2 in the expansion phase in the course of cell-based cartilage repair strategies, may result in a repair tissue with higher quality by increasing the content of glycosaminoglycans. ß

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Hypoxia-induced hyaluronan synthesis by articular chondrocytes: the role of nitric oxide

Abstract: Endogenous NO synthesis plays an important role in hypoxia-enhanced HA synthesis.

Cited by 29 publications

References 35 publications

TGF-β2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions

TGF-β2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions

Oxygen, nitric oxide and articular cartilage

Hypoxic expansion promotes the chondrogenic potential of articular chondrocytes

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