Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

Takeshita, Nobuaki; Yoshimi, Eiji; Hatori, Chie; Kumakura, Fumiyo; Seki, Nobuo; Shimizu, Yoshiyuki

doi:10.1254/jphs.10319fp

Cited by 20 publications

(20 citation statements)

References 44 publications

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“…Several authors have reported that ROCKi treatment increases glycosaminoglycan synthesis and expression of chondrogenic marker genes in mouse chondrocytic ATDC5 cells (30,31). The ROCK inhibitor AS1892802 prevents cartilage damage in a rat osteoarthritic disorder model (37). .…”

Section: Discussionmentioning

confidence: 99%

ROCK inhibition enhances aggrecan deposition and suppresses matrix metalloproteinase-3 production in human articular chondrocytes

Furumatsu

Matsumoto-Ogawa

Tanaka

et al. 2014

Connective Tissue Research

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Homeostasis of articular cartilage is maintained by a balance between catabolism and anabolism. Matrix metalloproteinase-3 (MMP-3) catabolism of cartilaginous extracellular matrix (ECM), including aggrecan (AGN), is an important factor in osteoarthritis progression. We previously reported that inhibition of Rho-associated coiled-coil forming kinase (ROCK), an effector of Rho family GTPases, activates the chondrogenic transcription factor SRY-type high-mobility-group box (SOX) 9 and prevents dedifferentiation of monolayer-cultured chondrocytes. We hypothesized that ROCK inhibition prevents chondrocyte dedifferentiation by altering the transcriptional balance between MMP-3 and AGN. Normal human articular chondrocytes were cultured in the presence or absence of ROCK inhibitor (ROCKi, Y-27632). Expression of MMP-3 and AGN during monolayer cultivation was assessed by quantitative real-time PCR and western blot analysis. Chondrogenic redifferentiation potential of ROCKi-treated chondrocytes was evaluated by immunohistological analysis of pellet cultures. ROCKi treatment suppressed MMP-3 expression in monolayer- and pellet-cultured chondrocytes but increased AGN expression. Chromatin immunoprecipitation revealed that the association between transcription factors E26 transformation specific (ETS)-1 and SOX9 and their target genes MMP-3 and AGN, respectively, was affected by ROCKi treatment. ROCKi decreased the association between ETS-1 and its binding sites on the MMP-3 promoter, whereas ROCKi promoted the interaction between SOX9 and the AGN promoter. Our results suggest that ROCK inhibition may have an important role in modulating the balance between degradation and synthesis of cartilaginous ECM, a finding that may facilitate development of techniques to prepare differentiated chondrocytes for cartilage regeneration therapy.

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Section: Discussionmentioning

confidence: 99%

ROCK inhibition enhances aggrecan deposition and suppresses matrix metalloproteinase-3 production in human articular chondrocytes

Furumatsu

Matsumoto-Ogawa

Tanaka

et al. 2014

Connective Tissue Research

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“…Conditional knock-down of Vegf attenuates surgically-induced osteoarthritis in mice, with intra-articular anti-VEGF antibodies as well as oral administration of the VEGFR2 kinase inhibitor Vandetanib suppressing osteoarthritis progression 33 . In a rat model of osteoarthritis, a rho kinase inhibitor was found to reduce knee cartilage damage 34 . Finally, there is a well-established effect of smoking on osteoarthritis 9,35 .…”

Section: Candidate Therapeutic Compoundsmentioning

confidence: 99%

Decoding the genomic basis of osteoarthritis

Steinberg

Southam

Butterfield

et al. 2019

Preprint

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Osteoarthritis is a serious joint disease that causes pain and functional disability for a quarter of a billion people worldwide 1 , with no disease-stratifying tools nor modifying therapy. Here, we use primary chondrocytes, synoviocytes and peripheral blood from patients with osteoarthritis to construct a molecular quantitative trait locus map of gene expression and protein abundance in disease. By integrating data across omics levels, we identify likely effector genes for osteoarthritis-associated genetic signals. We detect stark molecular differences between macroscopically intact (low-grade) and highly degenerated (high-grade) cartilage, reflecting activation of the extracellular matrix-receptor interaction pathway. Using unsupervised consensus clustering on transcriptome-wide sequencing, we identify molecularly-defined patient subgroups that correlate with clinical characteristics. Between-cluster differences are driven by inflammation, presenting the opportunity to stratify patients on the basis of their molecular profile for tailored intervention. We construct and validate a 7-gene classifier that reproducibly distinguishes between these disease subtypes. Finally, we identify potentially actionable compounds for disease modification and drug repositioning. Our findings contribute to both patient stratification and therapy development in this globally important area of unmet need.

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“…In the MIA-induced knee OA model, ABC294640 57 , a selective inhibitor of sphingosine kinase-2; AS1892802 58, 59 , which rarely penetrates the central nervous tissue and is a selective Rho kinase inhibitor; and MEN16132 60 , a kinin B(2) receptor antagonist, significantly improved weight bearing of the injected limb and alleviated cartilage degradation. Systemic co-administration of the selective positive allosteric modulator NS-9283 enhanced the analgesic potency of the nicotinic acetylcholine receptor (nAChR) α4β2 agonist ABT-594 5-fold 61 .…”

Section: Peripheral Mechanismsmentioning

confidence: 99%

Osteoarthritis pain mechanisms: basic studies in animal models

Zhang

Ren

Dubner

2013

Osteoarthritis and Cartilage

135

112

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Osteoarthritis (OA) is a complex and painful disease of the whole joint. At present there are no satisfying agents for treating OA. The current standard of care mainly involves managing and alleviating its symptoms. Mechanisms of OA pain have been studied in rodent knee OA models produced by intra-knee injection of the chondrocyte glycolytic inhibitor mono-iodoacetate, surgery, or spontaneous development in some species. These models are clinically relevant in terms of histological damage and functional changes, and are used to study mechanisms underlying mechanical, thermal, ambulatory, body weight supporting-evoked, and ongoing OA pain. Recent peripheral, spinal, and supraspinal biochemical and electrophysiological studies in these models suggest that peripheral pro-inflammatory mediators and neuropeptides sensitize knee nociceptors. Spinal cytokines and neuropeptides promote OA-associated pain, and peripheral and spinal cannabinoids inhibit OA pain respectively through cannabinoid-1 (CB1) and CB1/CB2 receptors. TRPV1 and metalloproteinases contribute and supraspinal descending facilitation of 5-HT/5-HT 3 receptors may also contribute to OA pain. Conditioned place preference tests demonstrate that OA pain induces aversive behaviors suggesting brain involvement in OA pain. During OA, brain functional connectivity is enhanced, but at present it is unclear how this change is related to OA pain.

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Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

Cited by 20 publications

References 44 publications

ROCK inhibition enhances aggrecan deposition and suppresses matrix metalloproteinase-3 production in human articular chondrocytes

ROCK inhibition enhances aggrecan deposition and suppresses matrix metalloproteinase-3 production in human articular chondrocytes

Decoding the genomic basis of osteoarthritis

Osteoarthritis pain mechanisms: basic studies in animal models

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