Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3

Chanalaris, Anastasios; Doherty, Christine; Bambridge, Gabriel; Wren, Stephen P.; Nagase, Hideaki; Troeberg, Linda

doi:10.1124/mol.117.109397

Cited by 17 publications

(11 citation statements)

References 39 publications

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“…Recent work suggested that the interaction of suramin and TIMP3 inhibited endocytosis of TIMP3 mediated by its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1. 27 Although we cannot exclude additional effects of suramin on articular chondrocytes, 28–30 our data and the work of Chanalaris suggest that interaction with TIMP3 is the main mechanism involved.…”

Section: Discussionmentioning

confidence: 68%

“…Moreover, TIMP3 has the unique ability to bind to the ECM in cartilage, in contrast to the other TIMPs (TIMP1, TIMP2 and TIMP4) that diffuse freely within the matrix. 27 The N-terminus of TIMP3 contains a highly basic region that is known to interact with negatively charged sulfated ECM components. 25 26 These unique characteristics position TIMP3 as the main inhibitor of the ECM turnover.…”

Section: Discussionmentioning

confidence: 99%

“… 26 Parallel and independent to our study, Chanalaris et al demonstrated that suramin can prevent ex vivo cartilage degradation by increasing TIMP3 levels and preventing TIMP3 endocytosis. 27 In addition, suramin could also inhibit purinergic receptors, 28 has been linked with inhibition of Wnt signalling 29 and can interact with and inhibit fibroblast growth factor-2. 30 Based on these different characteristics, we hypothesised that suramin may have cartilage-protective properties.…”

Section: Introductionmentioning

confidence: 99%

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Suramin increases cartilage proteoglycan accumulation in vitro and protects against joint damage triggered by papain injection in mouse knees in vivo

Guns¹,

Monteagudo²,

Kvasnytsia³

et al. 2017

RMD Open

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ObjectivesSuramin is an old drug used for the treatment of African sleeping sickness. We investigated therapeutic repositioning of suramin to protect against cartilage damage, as suramin may interact with tissue inhibitor of metalloproteinase-3 (TIMP3).MethodsIn vitro extracellular matrix (ECM) accumulation and turnover in the presence or absence of suramin were studied in the ATDC5 micromass model of chondrogenesis and in pellet cultures of human articular chondrocytes from osteoarthritis and control patients, by gene expression, protein analysis, colorimetric staining, immunoprecipitation, fluorimetric analysis and immunohistochemistry. To study suramin in vivo, the drug was injected intra-articularly in the papain model of joint damage. Disease severity was analysed by histology, immunohistochemistry and contrast-enhanced nanofocus CT.ResultsIn ATDC5 micromasses, suramin increased TIMP3 levels and decreased the activity of matrix metalloproteinases (MMPs) and aggrecanases. Suramin treatment resulted in increased glycosaminoglycans. This effect on the ECM was blocked by an anti-TIMP3 antibody. Direct interaction between suramin and endogenous TIMP3 was demonstrated in immunoprecipitates. Mice treated intra-articularly with suramin injections showed reduced cartilage damage compared with controls, with increased TIMP3 and decreased MMP and aggrecanase activity. Translational validation in human chondrocytes confirmed increased TIMP3 function and reduced cartilage breakdown after suramin treatment.ConclusionSuramin prevented loss of articular cartilage in a mouse model of cartilage damage. The effects appear to be mediated by a functional increase of TIMP3 and a subsequent decrease in the activity of catabolic enzymes. Thus, suramin repositioning could be considered to prevent progressive cartilage damage and avoid evolution toward osteoarthritis.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Suramin increases cartilage proteoglycan accumulation in vitro and protects against joint damage triggered by papain injection in mouse knees in vivo

Guns¹,

Monteagudo²,

Kvasnytsia³

et al. 2017

RMD Open

View full text Add to dashboard Cite

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“…Suramin, historically used as antiparasitic and antihelminthic drug, is able to restore the expression of chondroprotective tissue inhibitor of metalloproteinase (TIMP)-3, thereby inhibiting OA cartilage degradation by MMPs. 98 The direct inhibition of inflammation by neutralizing pro-inflammatory cytokines such as IL-1β and TNFα was less effective in OA. 99 Anti-inflammatory cytokines could antagonize proinflammatory cytokine effects.…”

Section: Therapeutically Addressed Signaling Pathways Of Oamentioning

confidence: 99%

Experimental Therapeutics for the Treatment of Osteoarthritis

Schulze‐Tanzil

2021

JEP

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Osteoarthritis (OA) therapy remains a large challenge since no causative treatment options are so far available. Despite some main pathways contributing to OA are identified its pathogenesis is still rudimentary understood. A plethora of therapeutically promising agents are currently tested in experimental OA research to find an opportunity to reverse OA-associated joint damage and prevent its progression. Hence, this review aims to summarize novelly emerging experimental approaches for OA. Due to the diversity of strategies shown only main aspects could be summarized here including herbal medicines, nanoparticular compounds, growth factors, hormones, antibody-, cell-and extracellular vesicle (EV)-based approaches, optimized tools for joint viscosupplementation, genetic regulators such as si-or miRNAs and promising combinations. An abundant multitude of compounds obtained from plants, environmental, autologous or synthetic sources have been identified with anabolic, anti-inflammatory,-catabolic and anti-apoptotic properties. Some ubiquitous signaling pathways such as wingless and Integration site-1 (Wnt), Sirtuin, Tolllike receptor (TLR), mammalian target of rapamycin (mTOR), Nuclear Factor (NF)-κB and complement are involved in OA and addressed by them. Hyaluronan (HA) provided benefit in OA since many decades, and novel HA formulations have been developed now with higher HA content and long-term stability achieved by cross-linking suitable to be combined with other agents such as components from herbals or chemokines to attract regenerative cells. pH-or inflammation-sensitive nanoparticular compounds could serve as versatile slowrelease systems of active compounds, for example, miRNAs. Some light has been brought into the intimate regulatory network of small RNAs in the pathogenesis of OA which might be a novel avenue for OA therapy in future. Attraction of autologous regenerative cells by chemokines and exosome-based treatment strategies could also innovate OA therapy.

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“…Interestingly, a different therapeutic strategy involves reducing TIMP-3 binding to LRP-1, thereby increasing its level in the ECM. TIMP-3 mutants engineered to resist endocytosis have prolonged chondroprotective activity 106 , and the chemical suramin, which binds to TIMP-3 and reduces its capacity to be endocytosed, has chondroprotective effects 107 .…”

Section: Recent Advances In Mmp-13 Protein Regulation and Inhibitionmentioning

confidence: 99%

Recent advances in understanding the regulation of metalloproteinases

2019

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Metalloproteinases remain important players in arthritic disease, in part because members of this large enzymatic family, namely matrix metalloproteinase-1 (MMP-1) and MMP-13, are responsible for the irreversible degradation of articular cartilage collagen. Although direct inhibition of MMPs fell out of vogue with the initial clinical disappointment of the first generation of compounds, interest in other mechanisms that control these important enzymes has always been maintained. Since these enzymes are critically important for tissue homeostasis, their expression and activity are tightly regulated at many levels, not just by direct inhibition by their endogenous inhibitors the tissue inhibitors of metalloproteinases (TIMPs). Focussing on MMP-13, we discuss recent work that highlights new discoveries in the transcriptional regulation of this enzyme, from defined promoter functional analysis to how more global technologies can provide insight into the enzyme’s regulation, especially by epigenetic mechanisms, including non-coding RNAs. In terms of protein regulation, we highlight recent findings into enzymatic cascades involved in MMP-13 regulation and activation. Importantly, we highlight a series of recent studies that describe how MMP-13 activity, and in fact that of other metalloproteinases, is in part controlled by receptor-mediated endocytosis. Together, these new discoveries provide a plethora of novel regulatory mechanisms, besides direct inhibition, which with renewed vigour could provide further therapeutic opportunities for regulating the activity of this class of important enzymes.

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Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3

Cited by 17 publications

References 39 publications

Suramin increases cartilage proteoglycan accumulation in vitro and protects against joint damage triggered by papain injection in mouse knees in vivo

Suramin increases cartilage proteoglycan accumulation in vitro and protects against joint damage triggered by papain injection in mouse knees in vivo

Experimental Therapeutics for the Treatment of Osteoarthritis

Recent advances in understanding the regulation of metalloproteinases

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