Effects of Controlling Abnormal Joint Movement on Expression of MMP13 and TIMP-1 in Osteoarthritis

Onitsuka, Katsuya; Murata, Kenji; Kokubun, Takanori; Fujiwara, Shuhei; Nakajima, Aya; Morishita, Yuri; Kanemura, Naohiko

doi:10.1177/1947603518783449

Cited by 18 publications

(23 citation statements)

References 31 publications

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“…Interestingly, MMP13 not only increases with IL-1β, but there is evidence that mechanical induction is also involved in its upregulation 59,60 , and in fact MMP13 is upregulated early in a rat model for DDH 29 , with a similar staining pattern to the one we observed. We detected more MMP13 in undamaged DDH-OA compared to undamaged OA-only, and both samples had similar aggrecan and collagen II staining, indicating that the increase in MMP13 is an early event, like that observed in a rat model for DDH 29 .…”

Section: Discussionsupporting

confidence: 82%

Early-Onset Osteoarthritis originates at the chondrocyte level in Hip Dysplasia

Hernández

Wells

Usheva

et al. 2020

Sci Rep

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Subjects with developmental dysplasia of the hip (DDH) often show early-onset osteoarthritis (oA); however, the molecular mechanisms underlying this pathology are not known. We investigated whether cellular changes in chondrocytes from oA cartilage can be detected in chondrocytes from DDH cartilage before histological manifestations of degeneration. We characterized undamaged and damaged articular cartilage from 22 participants having hip replacement surgery with and without DDH (9 DDH-OA, 12 OA-only, one femoral fracture). Tissue immunostaining revealed changes in damaged oA-only cartilage that was also found in undamaged DDH-oA cartilage. chondrocytes in situ from both groups show: (i) thicker fibers of vimentin intermediate filaments, (ii) clusters of integrin α 5 β 1 , (iii) positive MMP13 staining and (iv) a higher percentage of cells expressing the serine protease HtrA1. Further characterization of the extracellular matrix showed strong aggrecan and collagen II immunostaining in undamaged DDH cartilage, with no evidence of augmented cell death by activation of caspase 3. These findings suggest that early events in DDH cartilage originate at the chondrocyte level and that DDH cartilage may provide a novel opportunity to study these early changes for the development of therapeutic targets for oA. Although aging is among the various factors associated with the development of Osteoarthritis (OA) 1 , the incidence of OA has been increasing in younger populations. One study projected that the percentage of patients younger than 65 years old requiring total hip arthroplasty would increase from 41% in 2006 to 52% in 2030 2. These younger patients have a number of etiologies, including those with developmental dysplasia of the hip (DDH). In this condition, abnormal biomechanics leads to anomalous stress distribution within the hip joint and subsequent damage to the joint tissues including articular cartilage 3-6 and DDH is considered to be part of the congenital-biomechanical causes of OA 7. Chondrocytes, the cells of cartilage, are metabolically stimulated by different forms of mechanical loading including strain, shear, compression, tension, and hydrostatic loads, all of which are related to the structural and mechanical integrity of the joint. At the tissue-level, the extracellular matrix (ECM) 8 , composed mostly of collagen II and proteoglycans, gives mechanical integrity, while at the cellular-level the cytoskeleton fulfills this role, with vimentin intermediate filaments playing a major function 9,10. Mechanical load, in turn, regulates both cytoskeleton dynamics 11,12 and the synthesis of key ECM proteins 13,14. Of the key ECM components regulating mechanical signals to chondrocytes, fibronectin mediates pathways associated with cell growth and survival, for example promoting chondrocyte survival via integrin α 5 β 1 binding 15. However, in contrast, fibronectin fragments, produced via cleavage by proteases such as the High-Temperature Requirement protein A1 (HtrA1) 16 , activate catabolic pathways 17,18. In...

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Section: Discussionsupporting

confidence: 82%

Early-Onset Osteoarthritis originates at the chondrocyte level in Hip Dysplasia

Hernández

Wells

Usheva

et al. 2020

Sci Rep

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“…The matrix of cartilage was modulated by enzymes and their inhibitors through a cascade of events. Among them, MMP‐13 is a crucial enzyme that is implicated in degrading ECM of cartilage, whereas TIMP‐1 is the specific inhibitor of MMP‐13 (Onitsuka et al, ). In the PBS group, the MMP‐13 level, as suggested by the percentage of positive cells after immunohistochemical staining, is significantly higher than the intact joints and joints treated with CM (Figure a,b), whereas the TIMP‐1 level was remarkably increased in the CM group compared with the two other groups (Figure c,d), making MMP‐13/TIMP‐1 significantly lower in the CM group than in the PBS group (Figure e).…”

Section: Resultsmentioning

confidence: 99%

“…The matrix of cartilage was modulated by enzymes and their inhibitors through a cascade of events. Among them, MMP-13 is a crucial enzyme that is implicated in degrading ECM of cartilage, whereas TIMP-1 is the specific inhibitor of MMP-13 (Onitsuka et al, 2018).…”

Section: Maintained the Balance Between Mmp-13 And Timp-1mentioning

confidence: 99%

Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy

Chen

Sun

et al. 2019

J Tissue Eng Regen Med

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Evidence accumulated that mesenchymal stem cell (MSC) therapy ameliorated osteoarthritis (OA) via paracrine effect, whereas conditioned medium (CM) of MSCs contains all the secretomes. In vitro studies have proved its therapeutic effect in OA, but few in vivo evidences were unveiled. This study investigated the effect of MSCs–CM in an animal model of OA. OA was induced by anterior cruciate ligament transaction and destabilization of the medial meniscus in 12 rats bilaterally. The CM group (N = 6) was administered with intraarticular injection of MSCs–CM weekly, whereas the phosphate‐buffered saline (PBS) group (N = 6) was injected with PBS. Six rats served as normal control and received sham operation with weekly PBS injection. Rats were sacrificed 8 weeks postoperatively. Gross and histological morphology were analysed. Microcomputed tomography was applied to assess the subchondral bone. Components of extracellular matrix (ECM) including type II collagen (Col II) and aggrecan, and ECM homeostasis‐related enzymes (metalloproteinase‐13 [MMP‐13] and tissue inhibitor of metalloproteinase‐1 [TIMP‐1]), as well as autophagy markers (Beclin‐1 and microtubule‐associated protein light chain 3) were evaluated immunohistochemically. Chondrocyte apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick‐end labelling staining. Gene expression of Col II, aggrecan, MMP‐13, and TIMP‐1 was confirmed by real‐time polymerase chain reaction. Morphological outcomes demonstrated remarkable articular‐protective effect of MSCs–CM. Well‐maintained subchondral bone structure, significantly more abundant cartilage matrix, notably decreased ratio of MMP‐13 to TIMP‐1, and inhibited chondrocyte apoptosis with enhanced autophagy were observed in the CM group compared with the PBS group. In conclusion, MSCs–CM demonstrated satisfactory effect in alleviating OA in rats via protecting the microarchitecture of subchondral bone, balancing the ratio of MMP‐13 to TIMP‐1 in cartilage, and enhancing autophagy, which might provide a new remedy against OA.

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“…Because aggrecan prevents degradation of collagen fibrils, its loss is an important event in early stage OA (Wilusz et al, 2014;Carballo et al, 2017). Matrix metalloproteinases (MMPs), particularly the collagenase matrix metalloproteinase 13 (MMP-13), are involved in degradation of type II collagen (Wang et al, 2013a;Onitsuka et al, 2018), and disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is responsible for degradation of aggrecan (Malfait et al, 2010;Verma and Dalal, 2011;Larkin et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

AMD3100 Attenuates Post-Traumatic Osteoarthritis by Maintaining Transforming Growth Factor-β1-Induced Expression of Tissue Inhibitor of Metalloproteinase-3 via the Phosphatidylinositol 3-Kinase/Akt Pathway

Shi

et al. 2020

Front. Pharmacol.

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AMD3100 is a small-molecule inhibitor of the C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) axis, while its role in aggrecan metabolism is unclear. We hypothesized that the AMD3100 modulates the transforming growth factor-b1 (TGF-b1)-induced expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) in chondrocytes. We evaluated expression of CXCL12/CXCR4 and TIMP-3 in the knee joints of rats with and without osteoarthritis (OA) by immunohistochemistry, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA). The rats were divided into sham control, destabilization of the medial meniscus/ AMD3100-treated (DMM/AMD3100-treated), and DMM/phosphate-buffered saline (PBS)treated groups. After 6 weeks, the rats were euthanized and subjected to histological and immunohistochemical analyses. Also, interleukin (IL)-1-pretreated primary chondrocytes were cultured in the presence of empty control (−, −), CXCL12a (+,−), CXCL12a + small interfering RNA (siRNA) CXCR4 (+,+), or CXCL12a + siNC (+NC), and the expression levels of target markers were evaluated by Western blotting and real-time reverse transcription PCR (RT-PCR). The CXCL12/CXCR4 levels were higher, and the expression of TIMP-3 was lower, in the OA rats compared to the healthy control rats. The rats in the DMM/AMD3100treated group revealed a markedly decreased immunological response and mild pathology. Treatment with CXCL12a increased expression of aggrecan and disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) and suppressed that of TIMP-3 in IL-1-pretreated primary chondrocytes. TGF-b1 increased expression of TIMP-3, and this increase was reversed by CXCL12a via the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, these effects were inhibited by the CXCR4 antagonist

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Effects of Controlling Abnormal Joint Movement on Expression of MMP13 and TIMP-1 in Osteoarthritis

Cited by 18 publications

References 31 publications

Early-Onset Osteoarthritis originates at the chondrocyte level in Hip Dysplasia

Early-Onset Osteoarthritis originates at the chondrocyte level in Hip Dysplasia

Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy

AMD3100 Attenuates Post-Traumatic Osteoarthritis by Maintaining Transforming Growth Factor-β1-Induced Expression of Tissue Inhibitor of Metalloproteinase-3 via the Phosphatidylinositol 3-Kinase/Akt Pathway

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