Disease‐Modifying Osteoarthritis Treatment With Interleukin‐1 Receptor Antagonist Gene Therapy in Small and Large Animal Models

Nixon, Alan J.; Grol, Matthew W.; Lang, Hayley M.; Ruan, Merry Z. C.; Stone, Adrianne; Begum, Laila; Chen, Yuqing; Dawson, Brian; Gannon, Francis H.; Plutizki, Stanislav; Lee, Brendan H. L.; Guse, Kilian

doi:10.1002/art.40668

Cited by 60 publications

(61 citation statements)

References 28 publications

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“…37 From a clinical perspective, joint function restoration and characteristic pain alleviation are more important than the structural or radiological indication of pathology. 39 In the in vivo study, the OA-induced group displayed joint space lessening, irregular osteophytes and calcification compared with those of the sham-operated group. 38 Furthermore, the use of micro-CT has effectively delivered the direct in situ imaging of joint articular cartilage in preclinical OA models and the evaluation of joint spaces, osteophyte construction and calcification on the articular cartilage surface.…”

Section: Discussionmentioning

confidence: 90%

“…38 Furthermore, the use of micro-CT has effectively delivered the direct in situ imaging of joint articular cartilage in preclinical OA models and the evaluation of joint spaces, osteophyte construction and calcification on the articular cartilage surface. 39 In the in vivo study, the OA-induced group displayed joint space lessening, irregular osteophytes and calcification compared with those of the sham-operated group. The pathological phenotypes were relieved after LIG was administered as demonstrated by micro-CT and confirmed by histological analysis.…”

Section: Discussionmentioning

confidence: 90%

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Ligustilide attenuates nitric oxide‐induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways

Zhou

Jiang

et al. 2019

J Cellular Molecular Medi

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Ligustilide ( LIG ) is the main lipophilic component of the Umbelliferae family of pharmaceutical plants, including Radix angelicae sinensis and Ligusticum chuanxiong. LIG shows various pharmacological properties associated with anti‐inflammation and anti‐apoptosis in several kinds of cell lines. However, the therapeutic effects of LIG on chondrocyte apoptosis remain unknown. In this study, we investigated whether LIG had an anti‐apoptotic activity in sodium nitroprusside ( SNP )‐stimulated chondrocyte apoptosis and could delay cartilage degeneration in a surgically induced rat OA model, and elucidated the potential mechanisms. In vitro studies revealed that LIG significantly suppressed chondrocyte apoptosis and cytoskeletal remodelling, which maintained the nuclear morphology and increased the mitochondrial membrane potential. In terms of SNP , LIG treatment considerably reduced the expression levels of cleaved caspase‐3, Bax and inducible nitric oxide synthase and increased the expression level of Bcl‐2 in a dose‐dependent manner. The LIG ‐treated groups presented a significantly suppressed expression of activating transcription factor 2 and phosphorylation of Jun N‐terminal kinase ( JNK ) and p38 mitogen‐activated protein kinase ( MAPK ). The inhibitory effect of LIG was enhanced by the p38 MAPK inhibitor SB 203580 or the JNK inhibitor SP 600125 and offset by the agonist anisomycin. In vivo studies demonstrated that LIG attenuated osteoarthritic cartilage destruction by inhibiting the cartilage chondrocyte apoptosis and suppressing the phosphorylation levels of activating transcription factor 2, JNK and p38 MAPK . This result was confirmed by histological analyses, micro‐ CT , TUNEL assay and immunohistochemical analyses. Collectively, our studies indicated that LIG protected chondrocytes against SNP ‐induced apoptosis and delayed articular cartilage degeneration by suppressing JNK and p38 MAPK pathways.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Ligustilide attenuates nitric oxide‐induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways

Zhou

Jiang

et al. 2019

J Cellular Molecular Medi

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“…To more accurately quantify the differences in tendon/ligament size between genotypes, we employed phase-contrast μCT to examine differences in patellar ligament volume between genotypes (Figure 1M,N) – a technique we previously used to examine soft tissues including articular cartilage in intact murine knee joints 20–23 . In 4-month-old mice, we observed a thinning of the patellar ligament compared to wildtype mice, with no notable changes in articular cartilage surface (Figure 1M).…”

Section: Resultsmentioning

confidence: 99%

“…To quantify tendon/ligament volume, knee joints were dissected from mice, stained with contrast agents, scanned by phase-contrast μCT, and analyzed using TriBON software (RATOC, Tokyo, Japan) as previously described for articular cartilage 20–23 . In addition to the articular surfaces (data not shown), we performed contrast-enhanced visualization of the patellar ligament using this protocol.…”

Section: Methodsmentioning

confidence: 99%

Tendon and Motor Phenotypes in theCrtap^-/-Mouse Model of Recessive Osteogenesis Imperfecta

Grol

Haelterman

Munivez

et al. 2020

Preprint

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24Osteogenesis imperfecta (OI) is a heterogeneous group of connective tissue disorders 25 characterized by variable short stature, skeletal deformities, low bone mass with increased bone 26 fragility, and motor deficits. The majority of cases are caused by mutations in type I collagen, or 27 by mutations that affect collagen processing and/or modification. Like bone, the extracellular 28 matrix of tendons and ligaments is largely made up of type I collagen; however, despite the fact 29 that a subset of OI patients presents with joint hypermobility, how tendon/ligament dysfunction 30 contributes to this is unknown. Here, we performed a detailed phenotypic characterization of the 31 flexor digitorum longus (FDL) tendon, Achilles tendon and patellar ligament in the Crtap mutant 32 mouse model of severe, recessive OI. Stable, pyridinoline collagen cross-links were increased by 33 5-to 10-fold in mutant tendons and ligaments. Collagen fibril size in all three structures was also 34 smaller in Crtap -/mice compared to wildtype or heterozygous littermates. Together, these 35 ultrastructural and biochemical changes resulted in thinner tendons and ligaments with increased 36 cellularity compared to controls, as assessed by histology. To examine how alterations in tendons 37 might affect motor function, we performed a battery of behavioral assays. During open field 38 assessment, Crtap -/mice exhibited reduced horizontal and vertical activity. Crtap -/mice also 39 exhibited motor impairments on the rotarod and grid footslip tests. In addition, Crtap -/mice had 40 reduced grip strength and displayed reduced time on the inverted grid test, indicating that they 41 are weaker than wildtype and heterozygous mice. In summary, these data demonstrate that the 42 tendons/ligaments of Crtap -/mice are pathologically altered compared to wildtype -a 43 phenotype that correlates with motor deficits and grip strength impairments. As such, Crtap -/-44 mice provide a preclinical model with which to examine downstream mechanisms and therapies 45 pertaining to tendon/ligament pathology and motor dysfunction for OI patients. 46 48 ligaments connect articulating bones to support joint alignment and function 1, 2 . The extracellular 49 matrix of tendons and ligaments is primarily composed of type I collagen as well as smaller 50 quantities of other collagens and proteoglycans 3 . During development, the collagen fibrils in 51 tendons and ligaments develop through addition and lengthening before transitioning to 52 appositional fusion of existing fibers with continued lengthening in post-natal life 4 . The synthesis 53 and assembly of this collagen-rich matrix is influenced by other small collagens and 54 proteoglycans as well as by the cross-linking chemistry of type I procollagen fibrils, which in 55 turn regulates fibril size and strength 5 . Like tendon and ligament, the organic matrix of bone 56 consists largely of type I collagen 6 , and disruptions in collagen synthesis and folding have been 57 shown to negatively impact its biochemical ...

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“…Recent publications from two independent groups have highlighted the importance of IL-1 signaling in various small and larger animal models of posttraumatic OA (22–25). For example, IL-1 receptor antagonist therapy significantly improved cartilage, synovial membrane parameters, and disease-modifying effects in the equine OA model (26). The role of translation control in the inflammatory response was examined in macrophages (27), but never in chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

Katsara

Attur²,

Kolupaeva³

2019

Preprint

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As world population growing older, burden of age-related conditions soars. One of them is osteoarthritis (OA), a debilitating joint disease with no effective treatment. Articular cartilage degeneration is a central event in OA, and changes in expression of many genes in OA cartilage are well-documented. Still, the specific mechanisms are rarely known. We showed that in OA cartilage the increased abundance of many proteins, including extracellular matrix protein Fibronectin (Fn1) and an orphan nuclear receptor Nr4a1 is translationally controlled and requires inactivation of 4EBP, an inhibitor of cap-dependent translation. Importantly, intra-articular injection of the translation inhibitor 4E1RCat reduces Fn1 and Nr4a upregulation in a rodent OA model and delays cartilage degeneration. Our results support the hypothesis that maintaining proper translational control is an important homeostatic mechanism, the loss of which contributes to OA development.Recent publications from two independent groups have highlighted the importance of IL-1 signaling in various small and larger animal models of posttraumatic OA (22)(23)(24)(25). For example, IL-1 receptor antagonist therapy significantly improved cartilage, synovial membrane parameters, and disease-modifying effects in the equine OA model (26). The role of translation control in the inflammatory response was examined in macrophages (27), but never in chondrocytes. We therefore used polysome profiling to assess the translational landscape of IL-1β treated primary articular chondrocytes. In polysomal profiling, actively translated mRNAs bound by several ribosomes (polysomes) are separated from "free" mRNA and the 80S monosomes by sucrose gradient centrifugation. This allows determining the translational status of a specific mRNA. Potential clinical relevance of several identified translationally controlled targets, such as Fn and an orphan receptor Nr4a1, was tested in diseased cartilage and in a rodent model of post-traumatic OA. To demonstrate the importance of translational control for cartilage homeostasis, we injected intra-articularly an inhibitor of cap-dependent translation. This treatment significantly delays OA progression. Our findings therefore reveal that translational control, acting at Fn and Nr4a1 among other targets, is essential for maintaining cartilage homeostasis.Moreover, targeting translational apparatus represents a new strategy to treat/prevent OA, particularly as it opens up the possibility to target simultaneously a pool of functionally distinct proteins. MATERIALS AND METHODSIsolation and characterization of translationally active pool of mRNAs by polysome fraction analysis, library preparation, and sequencing. RAC was isolated and treated at the first passage as described previously (18). For 10 final minutes, cells were incubated with Cyclohexamide (100ug/ml) at 37 o C.Cells were collected, washed twice with ice-cold PBS supplemented with Cyclohexamide (100ug/ml) and lysed on ice for 10min in buffer "A" (SI). 2OD units of extract (3 independ...

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Disease‐Modifying Osteoarthritis Treatment With Interleukin‐1 Receptor Antagonist Gene Therapy in Small and Large Animal Models

Abstract: These data from OA models in small and large animals demonstrated safe symptomatic and disease-modifying treatment with an HDAd-expressing IL-1Ra. Furthermore, this study establishes HDAd as a vector for joint gene therapy.

Cited by 60 publications

References 28 publications

Ligustilide attenuates nitric oxide‐induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways

Ligustilide attenuates nitric oxide‐induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways

Tendon and Motor Phenotypes in theCrtap^-/-Mouse Model of Recessive Osteogenesis Imperfecta

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

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Disease‐Modifying Osteoarthritis Treatment With Interleukin‐1 Receptor Antagonist Gene Therapy in Small and Large Animal Models

Abstract: These data from OA models in small and large animals demonstrated safe symptomatic and disease-modifying treatment with an HDAd-expressing IL-1Ra. Furthermore, this study establishes HDAd as a vector for joint gene therapy.

Cited by 60 publications

References 28 publications

Ligustilide attenuates nitric oxide‐induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways

Ligustilide attenuates nitric oxide‐induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways

Tendon and Motor Phenotypes in theCrtap-/-Mouse Model of Recessive Osteogenesis Imperfecta

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

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Tendon and Motor Phenotypes in theCrtap^-/-Mouse Model of Recessive Osteogenesis Imperfecta