INT129964

Context Info Confidence 0.55 First Reported 2003 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 23 Total Number 23 Disease Relevance 6.48 Pain Relevance 4.21

peptidase activity (MMP13) extracellular space (MMP13) extracellular region (MMP13) Golgi apparatus (MMP13) proteinaceous extracellular matrix (MMP13) lysosome (MMP13)

Anatomy Link Frequency chondrocytes 1 cartilage 1 proximal 1 MMP13 (Homo sapiens)

Pain Link Frequency Relevance Heat metalloproteinase 466 100.00 Osteoarthritis 438 99.44 cytokine 115 98.88 Arthritis 114 95.76 Inflammatory stimuli 9 95.24 Inflammation 162 84.80 rheumatoid arthritis 159 84.24 cINOD 15 72.96 Potency 15 70.28 COX-2 inhibitor 21 63.52

Disease Link Frequency Relevance Heat Osteoarthritis 455 99.44 Chondrosarcoma 54 99.28 Hypertrophy 22 98.84 Arthritis 182 95.76 Hypercalcemia 74 95.32 INFLAMMATION 180 94.92 Cancer 87 94.52 Necrosis 22 94.32 Aging 4 91.60 Stomach Cancer 3 88.32

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Key:

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Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

and LG268 leads to modest but significant inhibition of MMP-1 and MMP-13, and a 12- to 24-hour pretreatment is necessary for maximum inhibition of MMP levels in these cells by the RXR ligand, LG268 [21].

Negative_regulation (inhibition) of MMP-13

1) Confidence 0.55 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0.23 Pain Relevance 0.12

With rosiglitazone, both the maximum level of inhibition of MMP-1 and MMP-13 (50% to 60%) and the pattern of MMP inhibition mirror those previously seen with LG268 treatment [21], suggesting that these compounds may be acting through similar mechanisms.

Negative_regulation (inhibition) of MMP-13

2) Confidence 0.55 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0.05 Pain Relevance 0.10

Real-time RT-PCR was used to quantify MMP mRNA, and Figure 1 demonstrates a dose-dependent inhibition of MMP-1 and MMP-13 mRNA levels in response to rosiglitazone treatment.

Negative_regulation (inhibition) of MMP-13

3) Confidence 0.55 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0.21 Pain Relevance 0.17

As shown in Figure 3a, treatment with either LG268 or rosiglitazone effectively reduced MMP-1 and MMP-13 mRNA by approximately 50%, and treatment with both ligands led to significantly greater inhibition (approximately 75%) than either drug alone.

Negative_regulation (reduced) of MMP-13

4) Confidence 0.55 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0 Pain Relevance 0

Because of the conserved nature of NHR domain structures, K364 may be the required RXR SUMOylation site for inhibition of MMP-1 and MMP-13 through this mechanism.

Negative_regulation (inhibition) of MMP-13

5) Confidence 0.40 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0.24 Pain Relevance 0

, and RXR homodimers bind to the DR-1 element [11], suggesting that all or any of these three dimers may be responsible for mediating the inhibitory effect of LG268 on MMP-1 and MMP-13.

Negative_regulation (effect) of MMP-13

6) Confidence 0.40 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0.15 Pain Relevance 0.04

, which appeared to be blocked by ligand treatment at the MMP-1 promoter but only modestly inhibited at the MMP-13 promoter (Figure 6).

Negative_regulation (inhibited) of MMP-13

7) Confidence 0.40 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0 Pain Relevance 0

Figure 3 shows a decrease in expression of MMP-1 and MMP-13 at the transcriptional level in cells treated with LG268 and rosiglitazone.

Negative_regulation (decrease) of MMP-13

8) Confidence 0.40 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0 Pain Relevance 0

-induced MMP-1 and MMP-13 transcription in the SW-1353 human chondrosarcoma cell line and is associated with a decrease in histone acetylation proximal to the transcription start site in the MMP-1 and MMP-13 promoters [21].

Negative_regulation (decrease) of MMP-13 in proximal associated with chondrosarcoma

9) Confidence 0.35 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2656243 Disease Relevance 0.21 Pain Relevance 0.06

Both the inhibition of MMP-13 and the potentiation of MMP-1 expression by fluoroquinolones were accompanied by corresponding changes in IL-1beta-stimulated MMP output.

Negative_regulation (inhibition) of MMP-13

10) Confidence 0.34 Published 2005 Journal Rheumatology (Oxford) Section Body Doc Link 16148020 Disease Relevance 0 Pain Relevance 0

Although a decrease in MMP-13 was noted with the MEK1/2 kinase inhibitor PD98059 at the concentration tested, it did not reach statistical significance.

Negative_regulation (decrease) of MMP-13

11) Confidence 0.29 Published 2005 Journal Arthritis Res Ther Section Body Doc Link PMC1065327 Disease Relevance 0 Pain Relevance 0

The results demonstrated: (a) that expression levels of the catabolic genes MMP-3 and MMP-13 were suppressed and (b) mRNA expression levels of anabolic genes of collagen II, SOX9 and aggrecan were increased.

Negative_regulation (suppressed) of MMP-13

12) Confidence 0.26 Published 2009 Journal Phytochemistry Section Abstract Doc Link 19118849 Disease Relevance 0.27 Pain Relevance 0.33

g/mL) significantly inhibited the MMP-13 level (Figure 4a).

Negative_regulation (inhibited) of MMP-13

13) Confidence 0.21 Published 2008 Journal Arthritis Res Ther Section Body Doc Link PMC2483463 Disease Relevance 0.19 Pain Relevance 0.05

With regard to structural mediators, diacerein decreased MMP-13 levels in synoviocytes but did not modify MMP-1 presence.

Negative_regulation (decreased) of MMP-13

14) Confidence 0.20 Published 2008 Journal Rheumatology (Oxford) Section Body Doc Link 18375401 Disease Relevance 0.06 Pain Relevance 0

This was associated with a downregulation of collagenases MMP-13 and MMP-1, proinflammatory cytokines IL-1?

Negative_regulation (downregulation) of MMP-13 associated with metalloproteinase and cytokine

15) Confidence 0.20 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC2206385 Disease Relevance 0.75 Pain Relevance 0.47

The group of patients receiving 1 mg of sCT exhibited significant decreases in the levels of CTX-II, C2C, and MMP-13.

Negative_regulation (decreases) of MMP-13

16) Confidence 0.18 Published 2006 Journal Arthritis Rheum. Section Body Doc Link 17009253 Disease Relevance 0.06 Pain Relevance 0

Agouron developed prinomastat (AG3340) [114], a MMP inhibitor with a Ki value in the picomolar range for the inhibition of MMP-2, MMP-9, MMP-13 and MMP-14, with lower activity against MMP-1 and MMP-7 [115].

Negative_regulation (inhibition) of MMP-13

17) Confidence 0.15 Published 2003 Journal Arthritis Res Ther Section Body Doc Link PMC154424 Disease Relevance 0.59 Pain Relevance 0.15

These inhibitors have been shown to be selective for two relatively distinct repertoires of MMPs – whereas inhibitor II inhibits MMP-1, MMP-3, MMP-7 and MMP-9, inhibitor III blocks MMP-1, MMP-2, MMP-3, MMP-7 and MMP-13 [26].

Negative_regulation (blocks) of MMP-13 associated with metalloproteinase

18) Confidence 0.12 Published 2006 Journal Arthritis Res Ther Section Body Doc Link PMC1779417 Disease Relevance 0.67 Pain Relevance 1.18

This is a broad-spectrum inhibitor with a nanomolar Ki against MMP-1, MMP-2, MMP-3, MMP-9, MMP-12 and MMP-13, and is chondroprotective in both the rabbit menisectomy model of OA and the guinea pig model of spontaneous OA [115].

Negative_regulation (inhibitor) of MMP-13 associated with osteoarthritis

19) Confidence 0.11 Published 2003 Journal Arthritis Res Ther Section Body Doc Link PMC154424 Disease Relevance 0.71 Pain Relevance 0.24

Our results showed that EGCG pretreatment of cultured human OA chondrocytes significantly inhibited the expression and activities of MMP-1 and MMP-13 in a dose-dependent manner [21].

Negative_regulation (inhibited) of MMP-13 in chondrocytes associated with osteoarthritis

20) Confidence 0.10 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2888220 Disease Relevance 0.43 Pain Relevance 0.27

General Comments

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