Induction of CEMIP in Chondrocytes by Inflammatory Cytokines: Underlying Mechanisms and Potential Involvement in Osteoarthritis

Ohtsuki, Takashi; Hatipoğlu, Ömer Faruk; Asano, Keiichi; Inagaki, Jiro; Nishida, Keiichiro; Hirohata, Satoshi

doi:10.3390/ijms21093140

Cited by 18 publications

(15 citation statements)

References 55 publications

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“…IL-1β can upregulate MMP3 and MMP9 and ADAMTs by activating IL-17, thereby promoting joint inflammation and inducing chondrocyte apoptosis [14]. Ohtsuki et al [15] observed that IL-1β is also involved in upregulating Cell migration-inducing hyaluronidase 1 (CEMIP), which induces the degradation of hyaluronan in ECM. Several miRNAs (miR-34a, miR-30a, miR-145, and miR-27a) are activated by IL-1β and participate in progression of OA by activating matrix-degrading enzymes and downstream inflammatory pathways such as MAPK and NF-κB [16].…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanisms of mechanical load-induced osteoarthritis

Fang

Zhou

Jin

et al. 2021

International Orthopaedics (SICOT)

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Introduction Mechanical loading enhances the progression of osteoarthritis. However, its molecular mechanisms have not been established. Objective The aim of this review was to summarize the probable mechanisms of mechanical load-induced osteoarthritis. Methods A comprehensive search strategy was used to search PubMed and EMBASE databases (from the 15th of January 2015 to the 20th of October 2020). Search terms included “osteoarthritis”, “mechanical load”, and “mechanism”. Results Abnormal mechanical loading activates the interleukin-1β, tumour necrosis factor-α, nuclear factor kappa-B, Wnt, transforming growth factor-β, microRNAs pathways, and the oxidative stress pathway. These pathways induce the pathological progression of osteoarthritis. Mechanical stress signal receptors such as integrin, ion channel receptors, hydrogen peroxide-inducible clone-5, Gremlin-1, and transient receptor potential channel 4 are present in the articular cartilages. Conclusion This review highlights the molecular mechanisms of mechanical loading in inducing chondrocyte apoptosis and extracellular matrix degradation. These mechanisms provide potential targets for osteoarthritis prevention and treatment.

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Section: Resultsmentioning

confidence: 99%

Molecular mechanisms of mechanical load-induced osteoarthritis

Fang

Zhou

Jin

et al. 2021

International Orthopaedics (SICOT)

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“…We also confirmed that this compound significantly suppressed the activation of MAPK signaling pathway molecules such as Erk1/2, p38, and JNK in IL-1β-induced OUMS27 cells in a concentration-dependent manner. MAPK signaling is one of the key signaling pathways that mediate inflammation responses and cartilage degradation and promote the pathological progression of OA [ 9 , 15 , 16 ]. These results indicate that 3-B2 could attenuate MMP and ADAMTS expression as well as chondrocyte inflammation by suppressing MAPK signaling pathway activation.…”

Section: Discussionmentioning

confidence: 99%

“…Cell lysates were centrifuged at 20,000× g for 15 min, and total protein concentrations were quantified using a Bio-Rad DC TM Protein Assay Kit (Bio-Rad Laboratories, Hercules, CA, USA), with bovine serum albumin used as the standard protein. Cell lysates were mixed with 4× reducing sample buffer, denatured at 95 °C for 5 min, separated on 10% SDS-PAGE gels, and transferred onto polyvinylidene difluoride (PVDF) membranes (Merck Millipore Ltd., Darmstadt, Germany) as previously described [ 15 , 39 ]. The primary antibodies were anti-MMP13 (1:400), anti-ERK (1:1000), anti-phospho-ERK (1:1000), anti-p38 (1:1000), anti-phospho-p38 (1:1000), anti-JNK (1:1000), anti-phospho-JNK (1:1000), and anti-β-actin (1:10,000).…”

Section: Methodsmentioning

confidence: 99%

“…Cell lysates were mixed with 4× reducing sample buffer, denatured at 95 • C for 5 min, separated on 10% SDS-PAGE gels, and transferred onto polyvinylidene difluoride (PVDF) membranes (Merck Millipore Ltd., Darmstadt, Germany) as previously described [15,39]. The primary antibodies were anti-MMP13 (1:400), anti-ERK (1:1000), anti-phospho-ERK (1:1000), anti-p38 (1:1000), anti-phospho-p38 (1:1000), anti-JNK (1:1000), anti-phospho-JNK (1:1000), and anti-β-actin (1:10,000).…”

Section: Western Blot Analysismentioning

confidence: 99%

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Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study

Inagaki

Nakano

Hatipoğlu

et al. 2022

IJMS

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Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

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“…They also indicated that HYAL1 and HYAL2 expression was up-regulated in OA chondrocytes; however, suppression of HYBID with siRNA eliminated HA depolymerization activity, and siRNA against HYAL1 and HYAL2 did not suppress HA depolymerization. Ohtsuki et al 16 reported that CEMIP/ HYBID expression was transiently increased by IL-1b stimulation in chondrocytic cells in vitro. These results suggest that HYBID is highly expressed in OA cartilage and synovial tissues and might play a central role in HA depolymerization under inflammatory conditions.…”

Section: Hyaluronidase In Developed Oa Potential Therapeutic Interventionmentioning

confidence: 99%

Pathophysiology of Hyaluronan Accumulation/Depolymerization in Osteoarthritic Joints

Nishida

2021

The American Journal of Pathology

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In healthy articular cartilage, the extracellular matrix (ECM) is properly maintained by the overall anabolic and catabolic balance of slow synthesis and degradation, a so-called homeostatic state, under the influence of synovial metabolism. Though the ECM of articular cartilage tissue contains low amounts of hyaluronan (HA), its main components are collagen, type II, IX, and XI, and proteoglycans, such as aggrecan. Nevertheless, HA plays crucial roles in cartilage, especially in retaining aggrecan in tissues. 1 Previous studies on ECM degradation in osteoarthritis (OA) focused on the degradation of the proteoglycan, aggrecan, 2 but not that of HA. The mechanism of HA synthesis in articular cartilage and synovium has been elucidated by the expression and functional analysis of hyaluronan synthase 1 to 3. However, research on the HA degradation system has not progressed because the main enzymes involved are not well understood. The research article by Momoeda et al, 3 in this issue of The American Journal of Pathology, provides new findings on the involvement of a novel hyaluronidase in OA development using genetically manipulated mice.Among the molecules in the hyaluronan-degrading enzyme (HYAL) family, HYAL1 and HYAL2 are widely expressed and have been hypothesized to be the major hyaluronidases involved in HA catabolism in somatic tissues. However, research data on HYAL1 and HYAL2 do not support them being the central hyaluronidases that cleave high-molecularweight (HMW) HA on the cell surface or extracellular space. This is because both HYAL1 and HYAL2 have enzymatic activity in the acidic condition, 4,5 whereas HYAL2, which has enzymatic activity on the cell membrane, has 50 times lower enzymatic activity than HYAL1. 6 Recently, two new molecules with strong hyaluronan degrading activity have been identified. First, KIAA1199, a deafness gene of unknown function, was reported to play a central role in HA degradation in the dermis of healthy skin

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Induction of CEMIP in Chondrocytes by Inflammatory Cytokines: Underlying Mechanisms and Potential Involvement in Osteoarthritis

Cited by 18 publications

References 55 publications

Molecular mechanisms of mechanical load-induced osteoarthritis

Molecular mechanisms of mechanical load-induced osteoarthritis

Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study

Pathophysiology of Hyaluronan Accumulation/Depolymerization in Osteoarthritic Joints

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