Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: relevance to post-traumatic osteoarthritis

Yang, Lixue; Wang, Yan; Chubinskaya, S.; Schoeberl, Birgit; Florine, E.; Kopesky, Paul W.; Grodzinsky, Alan J.

doi:10.1016/j.joca.2014.11.006

Cited by 105 publications

(181 citation statements)

References 54 publications

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“…The reduction of IL-1α induced sGAG loss in IGF-1 treated explants supports the findings of Li et al [47]. However, the sGAG suppression in the presented data is not as significant as shown by Li et al [47].…”

Section: Discussionsupporting

confidence: 90%

“…However, the sGAG suppression in the presented data is not as significant as shown by Li et al [47]. The lack of difference between single and continuous dose IGF-1 in sGAG loss and tissue metabolism, leads to the belief that the IGF-1 used was not effective.…”

Section: Discussioncontrasting

confidence: 59%

“…In monocultures, it was shown that a continuous dose of 250 ng/mL IL-1Ra caused significant reduction in sGAG and collagen loss, resulting in significant improvements in chondrocyte viability and metabolic activity through 22 days of culture compared to the IL-1α treated explants. IL-1α, which contributes to matrix degradation as well as inhibition of collagen II, aggrecan and other matrix protein synthesis, can therefore be inhibited by IL-1Ra as it directly intervenes with IL-1α activation [47,65]. By competitively binding to IL-1R1, IL-1Ra is able to prevent degradative measures caused by IL-1α [65].…”

Section: Discussionmentioning

confidence: 99%

“…This effect is enhanced further when IGF-1 is used in combination with DEX [47]. The concentration of IGF-1 (BioVision) used in experiments conducted was 100 ng/mL.…”

Section: Insulin-like Growth Factormentioning

confidence: 99%

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Development of in vitro joint tissue co-culture models for evaluating transport and biological crosstalk

Mehta¹

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Osteoarthritis (OA) affects the entire joint including tissues like synovium, cartilage, meniscus and bone. Abnormal mechanical stresses (from injury or aging) produce elevated levels of inflammatory cytokines that degrade joint tissues and cause excessive neovascularization and angiogenesis. It is critical to develop effective early interventions that target both synovium, the primary initiator and source of inflammation mediators, as well as tissues like cartilage, that are at risk of irreversible proteolytic degradation.Currently employed in vitro models, however, mostly use cartilage monocultures. Here we develop a co-culture model containing cartilage, synovium and meniscus to investigate biological and transport crosstalk between multiple joint tissues. Our data showed that co-culturing cartilage with synovium in the presence of inflammatory cytokine IL-1α, resulted in significantly higher chondrocyte death and reduced cell metabolism. Surprisingly, presence of synovium in co-culture helped significantly reduce chondrocyte nitrite production, suggesting release of anti-inflammatory factor by the synovium upon cytokine challenge. Presence of meniscus in co-culture did not present as significant of an effect as synovium did. However, culturing three tissues together increased cell death in cartilage by 3 weeks. These results confirm that significant biological crosstalk exists between various tissues. Thus co-culture systems should be preferred over monocultures to model the multiple complex pathways underlying OA.It is widely accepted that OA is a disease of the entire joint and that no single compound will be sufficient to treat every aspect of OA, thus requiring a combination of therapeutics. We therefore, investigated the role of receptor antagonist IL-1Ra, growth factor IGF-1 and chondrocyte differentiator Kartogenin (KGN) in suppressing IL-1α induced catabolic activity using monoculture or co-culture models. Drugs were introduced in either a single (mimicking one-time intraarticular injection) or continuous (mimicking multiple injections) dose regimen. Our results showed that single drug-dose was insufficient and that continuous dose, which helped maintain constant drug concentration over the entire culture period, is necessary to elicit an effective therapeutic response. This highlights the need for developing sustained and targeted drug-delivery systems for OA treatment. Future work will focus on designing strategies for co-targeting multiple tissues with multiple drugs to provide a combination OA therapy.iii ACKNOWLEDGEMENTS

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

“…This effect is enhanced further when IGF-1 is used in combination with DEX [47]. The concentration of IGF-1 (BioVision) used in experiments conducted was 100 ng/mL.…”

Section: Insulin-like Growth Factormentioning

confidence: 99%

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Development of in vitro joint tissue co-culture models for evaluating transport and biological crosstalk

Mehta¹

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“…Dexamethasone (Dex), a broad-spectrum corticosteroid, has potent anti-inflammatory effects, enhances chondrocyte differentiation and proteoglycan synthesis and reduces glycosaminoglycan loss in injured cartilage in vitro (Grodzinsky et al , 2017; Li et al , 2015; Lu et al , 2011) and in vivo (Huebner et al , 2014; Malfait et al , 2009). However, the precise actions of corticosteroids are highly dependent on the cumulative dose applied, complicating their therapeutic assessment.…”

Section: Introductionmentioning

confidence: 99%

Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis

Bajpayee¹,

Vega²,

Scheu³

et al. 2017

eCM

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Disease-modifying osteoarthritis drugs (DMOADs) should reach their intra-tissue target sites at optimal doses for clinical efficacy. The dense, negatively charged matrix of cartilage poses a major hindrance to the transport of potential therapeutics. In this work, electrostatic interactions were utilised to overcome this challenge and enable higher uptake, full-thickness penetration and enhanced retention of dexamethasone (Dex) inside rabbit cartilage. This was accomplished by using the positively charged glycoprotein avidin as nanocarrier, conjugated to Dex by releasable linkers. Therapeutic effects of a single intra-articular injection of low dose avidin-Dex (0.5 mg Dex) were evaluated in rabbits 3 weeks after anterior cruciate ligament transection (ACLT). Immunostaining confirmed that avidin penetrated the full cartilage thickness and was retained for at least 3 weeks. Avidin-Dex suppressed injury-induced joint swelling and catabolic gene expression to a greater extent than free Dex. It also significantly improved the histological score of cell infiltration and morphogenesis within the periarticular synovium. Micro-computed tomography confirmed the reduced incidence and volume of osteophytes following avidin-Dex treatment. However, neither treatment restored the loss of cartilage stiffness following ACLT, suggesting the need for a combinational therapy with a pro-anabolic factor for enhancing matrix biosynthesis. The avidin dose used caused significant glycosaminoglycan (GAG) loss, suggesting the use of higher Dex : avidin ratios in future formulations, such that the delivered avidin dose could be much less than that shown to affect GAGs. This charge-based delivery system converted cartilage into a drug depot that could also be employed for delivery to nearby synovium, menisci and ligaments, enabling clinical translation of a variety of DMOADs.

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Synthetic nanoscale electrostatic particles as growth factor carriers for cartilage repair

Shah

Geiger

Quadir

et al. 2016

Bioengineering & Transla Med

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The efficient transport of biological therapeutic materials to target tissues within the body is critical to their efficacy. In cartilage tissue, the lack of blood vessels prevents the entry of systemically administered drugs at therapeutic levels. Within the articulating joint complex, the dense and highly charged extracellular matrix (ECM) hinders the transport of locally administered therapeutic molecules. Consequently, cartilage injury is difficult to treat and frequently results in debilitating osteoarthritis. Here we show a generalizable approach in which the electrostatic assembly of synthetic polypeptides and a protein, insulin‐like growth factor‐1 (IGF‐1), can be used as an early interventional therapy to treat injury to the cartilage. We demonstrated that poly(glutamic acid) and poly(arginine) associated with the IGF‐1 via electrostatic interactions, forming a net charged nanoscale polyelectrolyte complex (nanoplex). We observed that the nanoplex diffused into cartilage plugs in vitro and stimulated ECM production. In vivo, we monitored the transport, retention and therapeutic efficacy of the nanoplex in an established rat model of cartilage injury. A single therapeutic dose, when administered within 48 hr of the injury, conferred protection against cartilage degradation and controlled interleukin‐1 mediated inflammation. IGF‐1 contained in the nanoplex was detected in the joint space for up to 4 weeks following administration and retained bioactivity. The results indicate the potential of this approach as an early intervention therapy following joint injury to delay or even entirely prevent the onset of osteoarthritis.

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Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: relevance to post-traumatic osteoarthritis

Cited by 105 publications

References 54 publications

Development of in vitro joint tissue co-culture models for evaluating transport and biological crosstalk

Development of in vitro joint tissue co-culture models for evaluating transport and biological crosstalk

Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis

Synthetic nanoscale electrostatic particles as growth factor carriers for cartilage repair

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