Tonic activation of hypoxia‐inducible factor 1α in avascular articular cartilage and implications for metabolic homeostasis

Brucker, Peter U.; Izzo, Nicholas J.; Chu, Constance R.

doi:10.1002/art.21346

Cited by 41 publications

(44 citation statements)

References 51 publications

(61 reference statements)

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“…HIF-1␣ immunostaining was heterogeneously detectable in nuclear, mixed nuclear/perinuclear, or perinuclear staining patterns, as described in bovine chondrocytes or other malignant cell types. 53,54 In contrast, a small number of ␣(I)-stained and a great number ␤-subunit-positive chondrocytes were distributed in all cartilage zones of normal and OA cartilage samples. Synthesis of ␣(I)-, ␣(II)-, and ␤-subunits of C-P4H was confirmed by conventional PCR and subsequent sequencing of the resulting PCR-products.…”

Section: Discussionmentioning

confidence: 93%

Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases

Grimmer

Balbus

Lang

et al. 2006

The American Journal of Pathology

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Osteoarthritic (OA) chondrocytes are metabolically active, displaying increased synthesis of type II collagen. Here, we show by immunohistochemistry and polymerase chain reaction that in comparison with healthy cartilage, OA articular chondrocytes exhibit increased in vivo synthesis of collagen prolyl-4-hydroxylase type II, a pivotal enzyme in collagen triple helix formation. Exposure of primary human articular chondrocytes to 1% oxygen enhanced accumulation of native type II collagen and stabilized hypoxia-inducible factor-1␣ (HIF-1␣). This effect was abolished by addition of the HIF-1 inhibitor 2-methoxyestradiol. Real-time polymerase chain reaction analyses of mRNAs from these cultures revealed increased transcript levels of both ␣-subunits of prolyl-4-hydroxylase (P4HA1, ϳ2-fold; P4HA2, ϳ2.3-fold) and of classical HIF-1 target genes (glucosetransporter-1, ϳ2.1-fold; phosphoglyceratekinase-1, ϳ2.2-fold). Treatment of hypoxic chondrocytes with 2-methoxyestradiol reduced transcriptional activity of HIF-1 and synthesis of ␣(II), and to a lesser extent ␣(I), subunits of collagen prolyl-4-hydroxylases. mRNA levels of type II collagen (Col2A1) and the ␤-subunit (P4HB) of prolyl-4-hydroxylase, however, displayed only modest changes at 1% oxygen. From these results and our in vivo data, we inferred that besides increased Articular hyaline cartilage is the most important component in synovial joints for frictionless joint motion. During movement, the articular cartilage is compressed by load and is then able to recover from this deformity. These unique biomechanical properties depend on the specific zonal architecture of articular cartilage as well as the extracellular matrix (ECM), which consists of two phases: solid and fluid phases. The main ECM components are proteoglycans, glycoproteins, and collagens, mainly type II collagen.1-3 Type II collagen is synthesized as a procollagen molecule with noncollagenous amino and carboxy extension peptides, by articular chondrocytes which represent the only living elements within hyaline cartilage. 4 Large type II collagen fibrils form a network with embedded proteoglycans, glycoproteins, water, and soluble ions. Since this collagen network is established in adults, the half-life of collagens is estimated to be over decades.Proper function of a load-bearing joint depends on the structural integrity of this highly specialized cartilage tissue and its ability to absorb and respond to mechanical stress. During the course of osteoarthritis, increased degradation processes of the ECM by mechanical factors as well as activity of metalloproteinases and aggrecanases have been observed. 5,6 Ultimately, destruction of large parts of the collagen network and ion-binding capacity via loss of negatively charged proteoglycans lead to a significantly decreased water-binding capability of the ECM. These biochemical changes are responsible for the devel-

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Section: Discussionmentioning

confidence: 93%

Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases

Grimmer

Balbus

Lang

et al. 2006

The American Journal of Pathology

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“…Oxygen concentrations measured in synovial fluid from rabbit and human knee joints were reported to be between 0%-10% (reviewed in 12 ) and based on model calculations, an oxygen concentration in the range of 1%-5% was predicted within adult human articular cartilage tissue in vivo. 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.…”

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confidence: 77%

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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“…This tissue, however, is destined to be replaced by bone via an angiogenesis-dependent process and may respond differently to articular cartilage. More recently, hypoxia-induced HIF-1α stabilisation has been shown in articular chondroytes, either in isolated cultured cells [20,31,59] or explants [14]. It may also be present during normoxia, but there is some controversy over whether its position is nuclear [20]-and thereby, functional-or perinuclear [14].…”

Section: Source Of Reactive Oxygen Speciesmentioning

confidence: 98%

“…More recently, hypoxia-induced HIF-1α stabilisation has been shown in articular chondroytes, either in isolated cultured cells [20,31,59] or explants [14]. It may also be present during normoxia, but there is some controversy over whether its position is nuclear [20]-and thereby, functional-or perinuclear [14]. HIF-1α may, thus, alter metabolism in articular chondrocytes during chronic alterations in O 2 tension and may play a role in disease such as osteoarthritis.…”

Section: Source Of Reactive Oxygen Speciesmentioning

confidence: 99%

Oxygen and reactive oxygen species in articular cartilage: modulators of ionic homeostasis

Gibson

Milner

White

et al. 2007

Pflugers Arch - Eur J Physiol

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Tonic activation of hypoxia‐inducible factor 1α in avascular articular cartilage and implications for metabolic homeostasis

Cited by 41 publications

References 51 publications

Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases

Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases

Hypoxic expansion promotes the chondrogenic potential of articular chondrocytes

Oxygen and reactive oxygen species in articular cartilage: modulators of ionic homeostasis

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