HIF-2α - a mediator of osteoarthritis?

Murphy, Christopher L.

doi:10.1038/cr.2010.99

Cited by 24 publications

(26 citation statements)

References 15 publications

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“…In contrast with HIF-1α [45], the role of HIF-2α during chondrogenesis is debatable [46]. It has been shown that HIF-2α can induce the expression of hypertrophic markers such as type X collagen and MMP13 in hypertrophic and osteoarthritic chondrocytes [47,48].…”

Section: Discussionmentioning

confidence: 99%

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

Portron

Hivernaud

Merceron

et al. 2015

Cell Physiol Biochem

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Background/Aims: Multipotent stem/stromal cells (MSC) are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion. Methods: Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O₂) or hypoxic (5%O₂) conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference). Results: Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion: These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.

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Section: Discussionmentioning

confidence: 99%

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

Portron

Hivernaud

Merceron

et al. 2015

Cell Physiol Biochem

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“…Previous work showed that NFκB is upstream of HIF-2α, but whether it is also upstream of ZIP8-mediated Zn 2+ influx has not yet been addressed, and NFκB does not have a defined role in ZIP8-mediated expression of MMPs (41). Moreover, the role in OA of the HIF-2α transcriptional signalling pathway remains controversial, given the anabolic effects of HIF-2α on chondrocytes (47–49). The ZIP8-mediated and MTF1 pathway mechanism would also benefit from further validation studies.…”

Section: Catabolic Reprogramming Of Chondrocytesmentioning

confidence: 99%

Emerging regulators of the inflammatory process in osteoarthritis

2014

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Chronic, low-grade inflammation in osteoarthritis (OA) contributes to symptoms and disease progression. Effective disease-modifying medical OA therapies are lacking, but better understanding inflammatory pathophysiology in OA could lead to transformative therapy. Networks of diverse innate inflammatory danger signals, including complement and alarmins, are activated in OA. Through inflammatory mediators, biomechanical cartilage injury and oxidative stress compromise chondrocyte viability and reprogram viable chondrocytes to hypertrophic differentiation and proinflammatory, and procatabolic responses in mechanistically similar ways. Integral to this reprogramming are certain ‘switching’ pathways in transcriptional signals, other than the well-characterized effects of NFκB and mitogen-activated protein kinase signalling. HIF-2α transcriptional signalling and ZIP8-mediated Zn2+ uptake, with downstream MTF1 transcriptional signalling, have been implicated in chondrocyte reprogramming, but further validation is required. Permissive factors in procatabolic reprogramming of OA chondrocytes by inflammatory mediators also have come to light, including impaired bioenergetics, such as altered mitochondrial function and decreased activity of the bioenergy sensors AMPK and SIRT1. These factors interact with molecular inflammatory responses and proteostasis mechanisms that normally resolve cell stress, such as the unfolded protein response and autophagy. Bioenergy-sensing by AMPK and SIRT1 modulates proteostasis and provides ‘stop signals’ for oxidative stress, inflammatory, and matrix catabolic processes in chondrocytes. The complexity of molecular inflammatory processes in OA, and the involvement of multiple inflammatory mediators in tissue repair responses, raises daunting questions about how to therapeutically target inflammatory processes and macroscopic inflammation in OA. Bioenergy sensing might provide a pragmatic ‘entry point’ for novel strategies to limit OA progression.

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“…As part of the signaling pathway, hypoxia inducible factor-2 alpha (HIF-2α) has been proposed as a catabolic factor that directly targets MMP-13 and iNOS through specific binding to the respective hypoxia-responsive elements [19–21]. However, the role of HIF-α isoforms (HIF-1α and HIF-2α) in OA pathogenesis is currently controversial and has led to species-dependent roles being proposed especially between murine and large mammals [22]. For example, HIF-2α has been shown by others to be responsible for hypoxic induction of cartilage matrix genes [22–25] and to be a potent regulator of autophagy in maturing mouse and human articular chondrocytes by acting as a brake to the autophagy accelerator function of HIF-1α [23].…”

Section: Introductionmentioning

confidence: 99%

Pentosan polysulfate inhibits IL-1β-induced iNOS, c-Jun and HIF-1α upregulation in canine articular chondrocytes

et al. 2017

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Osteoarthritic (OA) chondrocytes are shown to express inducible nitric oxide synthase (iNOS) which produces high concentrations of nitric oxide (NO), particularly when stimulated with proinflammatory cytokines. NO is involved in OA cartilage degradation. On the other hand, c-Jun N-terminal Kinase (JNK) pathway mediates the activation and transcription of c-Jun, which is required for interleukin-1 (IL-1)-induction of matrix metalloproteinases-13 (MMP-13) in OA pathogenesis. Therefore, the selective inhibition of iNOS and c-Jun is a promising target for treatment and prevention of OA. The purpose of the study was to investigate the inhibitory effects of pentosan polysulfate (PPS) on IL-1β-induced iNOS, c-Jun and HIF-α isoforms upregulation in canine articular chondrocytes (CACs). Primary (P0) chondrocytes were isolated and cultured from femoral head cartilages of three (3) dogs. First passage (P1) chondrocytes were preincubated with 0, 1, 5, 15 and 40 μg/mL of PPS for 4 hr before treatment with 10 ng/mL rhIL-1β for a further 8 hr. In addition, we evaluated the effects of single and multiple cytokine with or without LPS on iNOS protein induction. PPS significantly inhibited (P < 0.05) IL-1β-induced iNOS, c-Jun and HIF-1α mRNA upregulation in a dose-dependent pattern. iNOS mRNA was significantly inhibited at 15 and 40 μg/mL whereas c-Jun and HIF-1α were significantly downregulated at 5, 15 and 40 μg/mL of PPS compared to chondrocytes treated with only rhIL-1β. Intriguingly, CACs were recalcitrant to single IL-1β, TNF-α or LPS-induction of iNOS protein including to a combination of IL-1β+TNF-α, IL-1β+LPS except to TNF-α+LPS and IL-1β+TNF-α+LPS suggestive of a protective mechanism from iNOS detrimental effects on perpetuating OA. IL-1β+TNF-α+LPS-induced iNOS protein expression was significantly abrogated by PPS. We demonstrate for the first time that PPS is a novel inhibitor of IL-1β-induced iNOS, c-Jun, and HIF-1α mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA.

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HIF-2α - a mediator of osteoarthritis?

Cited by 24 publications

References 15 publications

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

Emerging regulators of the inflammatory process in osteoarthritis

Pentosan polysulfate inhibits IL-1β-induced iNOS, c-Jun and HIF-1α upregulation in canine articular chondrocytes

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