Production of tissue inhibitor of metalloproteinases 3 is selectively enhanced by calcium pentosan polysulfate in human rheumatoid synovial fibroblasts

Takizawa, Masayuki; Ohuchi, Eiko; Yamanaka, Hiroki; Nakamura, Hiroyuki; Ikeda, Eiji; Ghosh, Peter; Okada, Yasunori

doi:10.1002/1529-0131(200004)43:4<812::aid-anr11>3.0.co;2-y

Cited by 50 publications

(37 citation statements)

References 35 publications

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“…23,24,43 Apart from its antiinflammatory properties, 8,9,40,41,71,72,85 PPS is a potent leukocyte elastase 4 and aggrecanase (ADAMTS-4 and ADAMTS-5) inhibitor. [77][78][79][80] Pentosan polysulfate has been shown to mediate part of its antiinflammatory effects by downregulating TNF-a activity via the suppression of NF-Kb nuclear translocation and inhibition of the MAPKs pathways. 75,76,85 Since the levels of TNF-a 68 and ADAMTS-4/ADAMTS-5 51 are elevated in degenerative discs and have been implicated in the degradation of disc PGs, the combination of PPS with MPCs in the present study offered several potential advantages over the use of MPCs alone.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model

Oehme

Ghosh

Shimmon

et al. 2014

SPI

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Object Following microdiscectomy, discs generally fail to undergo spontaneous regeneration and patients may experience chronic low-back pain and recurrent disc prolapse. In published studies, formulations of mesenchymal progenitor cells combined with pentosan polysulfate (MPCs+PPS) have been shown to regenerate disc tissue in animal models, suggesting that this approach may provide a useful adjunct to microdiscectomy. The goal of this preclinical laboratory study was to determine if the transplantation of MPCs+PPS, embedded in a gelatin/fibrin scaffold (SCAF), and transplanted into a defect created by microdiscectomy, could promote disc regeneration. Methods A standardized microdiscectomy procedure was performed in 18 ovine lumbar discs. The subsequent disc defects were randomized to receive either no treatment (NIL), SCAF only, or the MPC+PPS formulation added to SCAF (MPCs+PPS+SCAF). Necropsies were undertaken 6 months postoperatively and the spines analyzed radiologically (radiography and MRI), biochemically, and histologically. Results No adverse events occurred throughout the duration of the study. The MPC+PPS+SCAF group had significantly less reduction in disc height compared with SCAF-only and NIL groups (p < 0.05 and p < 0.01, respectively). Magnetic resonance imaging Pfirrmann scores in the MPC+PPS+SCAF group were significantly lower than those in the SCAF group (p = 0.0213). The chaotropic solvent extractability of proteoglycans from the nucleus pulposus of MPC+PPS+SCAF-treated discs was significantly higher than that from the SCAF-only discs (p = 0.0312), and using gel exclusion chromatography, extracts from MPC+PPS+SCAF-treated discs also contained a higher percentage of proteoglycan aggregates than the extracts from both other groups. Analysis of the histological sections showed that 66% (p > 0.05) of the MPC+PPS+SCAF-treated discs exhibited less degeneration than the NIL or SCAF discs. Conclusions These findings demonstrate the capacity of MPCs in combination with PPS, when embedded in a gelatin sponge and sealed with fibrin glue in a microdiscectomy defect, to restore disc height, disc morphology, and nucleus pulposus proteoglycan content.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model

Oehme

Ghosh

Shimmon

et al. 2014

SPI

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“…Moreover, if a deficiency of TIMP3 is detrimental, could elevating its levels be beneficial in inflammatory conditions? Adenoviral delivery to rheumatoid synoviocytes has already been tested 4 , and at least one antiarthritic agent increases TIMP3 expression 15 . The work by Mohammed et al 5 should stimulate many more such investigations.…”

Section: Insights Into Inflammationmentioning

confidence: 99%

TIMP3 checks inflammation

Black

2004

Nat Genet

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“…36 The presence of TIMPs has been shown in RA synovial tissue. 9,18 Despite an increased expression of TIMPs in RA, 9,19 proteolytic degradation of the articular cartilage still occurs, suggesting an imbalance between MMP and TIMP activity in favor of the MMPs. Restoring the imbalance between MMP and TIMP activity within the rheumatoid synovium or changing it into a balance in favor of TIMP activity may, therefore, protect the articular cartilage and bone from MMP-mediated degradation.…”

Section: Introductionmentioning

confidence: 99%

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

Laan

Quax

Seemayer³

et al. 2003

Gene Ther

103

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Matrix metalloproteinases (MMPs) are believed to be pivotal enzymes in the invasion of articular cartilage by synovial tissue in rheumatoid arthritis (RA). Here, we investigated the effects of gene transfer of tissue inhibitors of metalloproteinases (TIMPs) on the invasiveness of RA synovial fibroblasts (RASF) in vitro and in vivo. Adenoviral vectors (Ad) were used for gene transfer. The effects of AdTIMP-1 and AdTIMP-3 gene transfer on matrix invasion were investigated in vitro in a transwell system. Cartilage invasion in vivo was studied in the SCID mouse coimplantation model for 60 days. In addition, the effects of AdTIMP-1 and AdTIMP-3 on cell proliferation were investigated. A significant reduction in invasiveness was demonstrated in vitro as well as in vivo in both the AdTIMP-1-and AdTIMP-3-transduced RASF compared with untransduced SF or SF that were transduced with control vectors. In vitro, the number of invading cells was reduced to 25% (Po0.001) in the AdTIMP-1-transduced cells and to 13% (Po0.0001) in the AdTIMP-3-transduced cells (% of untransduced cells). Cell proliferation was significantly inhibited by AdTIMP-3 and, less, by AdTIMP-1. In conclusion, overexpression of TIMP-1 and TIMP-3 by Ad gene transfer results in a marked reduction of the invasiveness of RASF in vitro and in the SCID mouse model. Apart from the inhibition of MMPs, a reduction in proliferation rate may contribute to this effect. These results suggest that overexpression of TIMPs, particularly TIMP-3 at the invasive front of pannus tissue, may provide a novel therapeutic strategy for inhibiting joint destruction in RA.

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Production of tissue inhibitor of metalloproteinases 3 is selectively enhanced by calcium pentosan polysulfate in human rheumatoid synovial fibroblasts

Cited by 50 publications

References 35 publications

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model

TIMP3 checks inflammation

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

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