Hypoxia Potentiates Anabolic Effects of Exogenous Hyaluronic Acid in Rat Articular Cartilage

Ichimaru, S.; Nakagawa, Shuji; Kishida, Tsunao; Shin‐Ya, Masaharu; Honjo, Kuniaki; Tsuchida, Shinji; Inoue, Hiroaki; Fujiwara, Hiroyoshi; Shimomura, Seiji; Mazda, Osam; Kubo, Toshikazu

doi:10.3390/ijms17071013

Cited by 11 publications

(16 citation statements)

References 36 publications

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“…Hyaluronic acid is composed of N -acetylglucosamine and d -glucuronic acid, which are linked via β-(1,3) bonds through dehydration polymerization. It is a major component of the ECM in connective tissue such as skin and eye lens and is used clinically to treat osteoarthritis [12]. As the HA polymer chain carries substantial negative charges, the molecules of HA completely unfold in water due to charge repulsion, occupying considerable space and enabling HA to absorb water 1000 times its own weight [13].…”

Section: Introductionmentioning

confidence: 99%

Dual Function of Glucosamine in Gelatin/Hyaluronic Acid Cryogel to Modulate Scaffold Mechanical Properties and to Maintain Chondrogenic Phenotype for Cartilage Tissue Engineering

Chen

Kuo

Wang

et al. 2016

IJMS

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Glucosamine (GlcN) fulfills many of the requirements as an ideal component in scaffolds used in cartilage tissue engineering. The incorporation of GlcN in a gelatin/hyaluronic acid (GH) cryogel scaffold could provide biological cues in maintaining the phenotype of chondrocytes. Nonetheless, substituting gelatin with GlcN may also decrease the crosslinking density and modulate the mechanical properties of the cryogel scaffold, which may be beneficial as physical cues for chondrocytes in the scaffold. Thus, we prepared cryogel scaffolds containing 9% GlcN (GH-GlcN9) and 16% GlcN (GH-GlcN16) by carbodiimide-mediated crosslinking reactions at −16 °C. The crosslinking density and the mechanical properties of the cryogel matrix could be tuned by adjusting the content of GlcN used during cryogel preparation. In general, incorporation of GlcN did not influence scaffold pore size and ultimate compressive strain but increased porosity. The GH-GlcN16 cryogel showed the highest swelling ratio and degradation rate in hyaluronidase and collagenase solutions. On the contrary, the Young’s modulus, storage modulus, ultimate compressive stress, energy dissipation level, and rate of stress relaxation decreased by increasing the GlcN content in the cryogel. The release of GlcN from the scaffolds in the culture medium of chondrocytes could be sustained for 21 days for GH-GlcN16 in contrast to only 7 days for GH-GlcN9. In vitro cell culture experiments using rabbit articular chondrocytes revealed that GlcN incorporation affected cell proliferation, morphology, and maintenance of chondrogenic phenotype. Overall, GH-GlcN16 showed the best performance in maintaining chondrogenic phenotype with reduced cell proliferation rate but enhanced glycosaminoglycans (GAGs) and type II collagen (COL II) secretion. Quantitative real-time polymerase chain reaction also showed time-dependent up-regulation of cartilage-specific marker genes (COL II, aggrecan and Sox9) for GH-GlcN16. Implantation of chondrocytes/GH-GlcN16 constructs into full-thickness articular cartilage defects of rabbits could regenerate neocartilage with positive staining for GAGs and COL II. The GH-GlcN16 cryogel will be suitable as a scaffold for the treatment of articular cartilage defects.

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Section: Introductionmentioning

confidence: 99%

Dual Function of Glucosamine in Gelatin/Hyaluronic Acid Cryogel to Modulate Scaffold Mechanical Properties and to Maintain Chondrogenic Phenotype for Cartilage Tissue Engineering

Chen

Kuo

Wang

et al. 2016

IJMS

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“…CD44, plays an important role in regulating multiple cellular functions (Ishida et al, 1997). It has previously been shown that hypoxia potentiated the anabolic effects of HA, including the redifferentiation of articular chondrocytes and synthesis of ECM, through enhancing CD44 expression and binding affinity (Ichimaru et al, 2016). Furthermore, previous research suggested that hypoxia could enhance the expression of CD44 via HIF-1α (Liang et al, 2017).…”

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confidence: 99%

“…With the development of tissue engineering technology, implantation of HA-based hydrogel is a novel biological treatment for early stage IDD. Various HA hydrogels have been investigated for their potential to replace and regenerate the NP through reducing inflammation response and nociceptive behaviour (Isa et al, 2015;Mohd et al, 2018), promoting ECM synthesis (Kim et al, 2015), and restoring biomechanical properties (Zhou et al, 2014). Furthermore, it has recently been shown that HA hydrogels could promote stem cell differentiation to NP-like cells and improve the efficacy of stem cells for NP regeneration (Chen et al, 2019;Peroglio et al, 2013).…”

mentioning

confidence: 99%

“…Some studies have explored the mechanism by which HA promotes NP regeneration. For example, HA could modulate the inflammatory receptor of IL-1R1, MyD88 and neurotrophin expression (Isa et al, 2015), or downregulate the catabolic marker ADAMTS4 (Kazezian et al, 2017). However, these studies assessing the biological effects and molecular mechanisms of HA for NP regeneration, have been performed under standard normoxic conditions, which is not representative of the physiological hypoxic environment in the intervertebral disc.…”

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confidence: 99%

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The effect of hyaluronic acid on nucleus pulposus extracellular matrix production through hypoxia-inducible factor-1α transcriptional activation of CD44 under hypoxia

Zhang¹,

Liu²,

Li³

et al. 2021

eCM

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Intervertebral disc degeneration (IDD) is the leading cause of low-back pain. Implantation of hyaluronic acid (HA) is potentially a therapeutic strategy for IDD, but its pharmacological effects and mechanism under hypoxic conditions remain unclear. In this study, the expression of extracellular matrix genes and proteins were enhanced in nucleus pulposus cells (NPCs) in the presence of HA under hypoxic condition, as shown by real-time reverse transcription-polymerase chain reaction, immunofluorescence staining, and dimethylmethylene blue assays. Moreover, the expression of CD44 was increased in the presence of both HA and hypoxia compared to either alone. Using a bioinformatic database, hypoxia inducible factor-1α (HIF-1α), a key transcription factor in the hypoxic condition, was found to have 4 predicted binding sites on the CD44 promoter. CD44 expression was significantly increased by treatment with cobalt chloride or dimethyloxalylglycine. Over-expression of HIF-1α in NPCs significantly up-regulated the expression of CD44. The binding site of HIF-1α in the CD44 promoter region, was identified by promoter truncation experiments and chromatin immunoprecipitation assays. Taken together, these results indicated that hypoxic conditions positively potentiated the ability of NPCs matrix synthesis in the presence of HA, which correlated with the increasing CD44 expression by HIF-1α transcriptional activation.

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“…In addition, the bioactivity of HMW‐HA for chondrocytes and synoviocytes have been studied, and the activity of HA has been shown to depend on its molecular weight. For instance, HA with a molecular weight (Mw) larger than approximately 7.0 × 10 5 to 8.0 × 10 5 Da enhanced the biosynthesis of the extra‐cellular matrix and the sensitivity to growth factor, whereas the expressions of some catabolic factors such as matrix metalloproteinases (MMPs) and inflammatory cytokines were suppressed in in vitro and in vivo experiments . These biological effects of HA are generally attributed to the stimulation of target cells via binding to HA receptors such as CD44.…”

Section: Introductionmentioning

confidence: 99%

Characterization of poly(L‐glutamic acid)‐grafted hyaluronan as a novel candidate medicine and biomedical device for intra‐articular injection

Muramatsu

Tajima

Kaneko

et al. 2017

J Biomedical Materials Res

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A novel hyaluronan (HA) derivative, poly(L-glutamic acid)-grafted hyaluronan (PGA-g-HA), was synthesized to improve the durability of conventional HA products for intra-articular injection. The purpose of this study was to investigate the characteristics of the novel HA derivative in terms of viscoelasticity, degradation behavior, non-immunogenicity, and bioactivity using preliminary in vitro and in vivo experiments. The storage modulus (G') and loss modulus (G″) of PGA-g-HA were similar to those of HA80 (approximately 8.0 × 10 Da) rather than those of original HA200 (approximately 2.0 × 10 Da). PGA-g-HA showed strong resistance against hyaluronidase hydrolysis compared to unmodified HA200. The immunogenicity resulting from grafting PGA to HA200 was not detected in bone marrow derived dendritic cells. The anti-inflammatory activity of PGA-g-HA was confirmed in IL-1β-stimulated chondrocytes. In addition, compared to unmodified HA200, the intra-articular injection of PGA-g-HA produced greater chondroprotective effects on a monoiodoacetic acid-induced model of rat knee osteoarthritis at two weeks after a single treatment. Therefore, PGA-g-HA is expected to be a promising medicine and biomedical device for intra-articular injection. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3006-3016, 2017.

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Hypoxia Potentiates Anabolic Effects of Exogenous Hyaluronic Acid in Rat Articular Cartilage

Cited by 11 publications

References 36 publications

Dual Function of Glucosamine in Gelatin/Hyaluronic Acid Cryogel to Modulate Scaffold Mechanical Properties and to Maintain Chondrogenic Phenotype for Cartilage Tissue Engineering

Dual Function of Glucosamine in Gelatin/Hyaluronic Acid Cryogel to Modulate Scaffold Mechanical Properties and to Maintain Chondrogenic Phenotype for Cartilage Tissue Engineering

The effect of hyaluronic acid on nucleus pulposus extracellular matrix production through hypoxia-inducible factor-1α transcriptional activation of CD44 under hypoxia

Characterization of poly(L‐glutamic acid)‐grafted hyaluronan as a novel candidate medicine and biomedical device for intra‐articular injection

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