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RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.

Yagishita N, Aratani S, Leach C, Amano T, Yamano Y, Nakatani K, Nishioka K, Nakajima T - Int. J. Mol. Med. (2012)

Bottom Line: We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway.Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA.Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

ABSTRACT
Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

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Effects of LS-101 and LS-102 in mouse CIA. DBA/1 mice immunized on day 0 and boosted onday 21 with type II collagen were treated with the vehicle alone, 0.25 mg/kgdexamethasone (Dex), or with 1.3, 4.0 mg/kg LS-101 or LS-102 from day 21 to 49. (A)Change in body weight. (B) The level of anti-type II collagen antibodies. (C) Totalarthritis score. (D) Histological arthritis score. Data are mean ± SEM (initialn=12; final n=7). *P<0.05,**P<0.01.
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f4-ijmm-30-06-1281: Effects of LS-101 and LS-102 in mouse CIA. DBA/1 mice immunized on day 0 and boosted onday 21 with type II collagen were treated with the vehicle alone, 0.25 mg/kgdexamethasone (Dex), or with 1.3, 4.0 mg/kg LS-101 or LS-102 from day 21 to 49. (A)Change in body weight. (B) The level of anti-type II collagen antibodies. (C) Totalarthritis score. (D) Histological arthritis score. Data are mean ± SEM (initialn=12; final n=7). *P<0.05,**P<0.01.

Mentions: To evaluate the in vivo efficacy of synoviolin inhibitors, we testedLS-101 and LS-102 in a mouse model of arthritis over a period of 28 days. No reduction ofbody weight was observed during the administration of these compounds (Fig. 4A). Moreover, the production ofanti-type II collagen antibodies resulting from type II collagen immunization in both theLS-101 and LS-102 group was comparable to that observed in the vehicle control group(Fig. 4B). Intraperitonealtreatment with LS-101 or LS-102 starting on day 21 reduced the clinical severity scorescompared to vehicle controls (Fig.4C). The efficacy was observed at both 1.3 mg/kg and 4.0 mg/kg doses in thisexperiment, although the protective effect of LS-101 at 1.3 mg/kg against CIA was strongerthan the same dose of LS-102. At 4.0 mg/kg, there was no difference in the effects betweenLS-101 and LS-102. Finally, histological analysis showed lower histological arthritisscores in mice treated with the synoviolin inhibitors compared with wild-type mice (Fig. 4D).


RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.

Yagishita N, Aratani S, Leach C, Amano T, Yamano Y, Nakatani K, Nishioka K, Nakajima T - Int. J. Mol. Med. (2012)

Effects of LS-101 and LS-102 in mouse CIA. DBA/1 mice immunized on day 0 and boosted onday 21 with type II collagen were treated with the vehicle alone, 0.25 mg/kgdexamethasone (Dex), or with 1.3, 4.0 mg/kg LS-101 or LS-102 from day 21 to 49. (A)Change in body weight. (B) The level of anti-type II collagen antibodies. (C) Totalarthritis score. (D) Histological arthritis score. Data are mean ± SEM (initialn=12; final n=7). *P<0.05,**P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042867&req=5

f4-ijmm-30-06-1281: Effects of LS-101 and LS-102 in mouse CIA. DBA/1 mice immunized on day 0 and boosted onday 21 with type II collagen were treated with the vehicle alone, 0.25 mg/kgdexamethasone (Dex), or with 1.3, 4.0 mg/kg LS-101 or LS-102 from day 21 to 49. (A)Change in body weight. (B) The level of anti-type II collagen antibodies. (C) Totalarthritis score. (D) Histological arthritis score. Data are mean ± SEM (initialn=12; final n=7). *P<0.05,**P<0.01.
Mentions: To evaluate the in vivo efficacy of synoviolin inhibitors, we testedLS-101 and LS-102 in a mouse model of arthritis over a period of 28 days. No reduction ofbody weight was observed during the administration of these compounds (Fig. 4A). Moreover, the production ofanti-type II collagen antibodies resulting from type II collagen immunization in both theLS-101 and LS-102 group was comparable to that observed in the vehicle control group(Fig. 4B). Intraperitonealtreatment with LS-101 or LS-102 starting on day 21 reduced the clinical severity scorescompared to vehicle controls (Fig.4C). The efficacy was observed at both 1.3 mg/kg and 4.0 mg/kg doses in thisexperiment, although the protective effect of LS-101 at 1.3 mg/kg against CIA was strongerthan the same dose of LS-102. At 4.0 mg/kg, there was no difference in the effects betweenLS-101 and LS-102. Finally, histological analysis showed lower histological arthritisscores in mice treated with the synoviolin inhibitors compared with wild-type mice (Fig. 4D).

Bottom Line: We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway.Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA.Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

ABSTRACT
Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

Show MeSH
Related in: MedlinePlus