Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular cysteine protease (paracaspase) that plays an integral role in innate and adaptive immunity. The phenothiazine mepazine has been shown to inhibit the proteolytic activity of MALT1 and is frequently used to...
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| Format: | Article |
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MDPI AG
2018-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/23/12/3144 |
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| author | Laura Meloni Lynn Verstrepen Marja Kreike Jens Staal Yasmine Driege Inna S. Afonina Rudi Beyaert |
| author_facet | Laura Meloni Lynn Verstrepen Marja Kreike Jens Staal Yasmine Driege Inna S. Afonina Rudi Beyaert |
| author_sort | Laura Meloni |
| collection | DOAJ |
| description | Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular cysteine protease (paracaspase) that plays an integral role in innate and adaptive immunity. The phenothiazine mepazine has been shown to inhibit the proteolytic activity of MALT1 and is frequently used to study its biological role. MALT1 has recently been suggested as a therapeutic target in rheumatoid arthritis. Here, we analyzed the effect of mepazine on the receptor activator of nuclear factor κ-B (RANK)-induced osteoclastogenesis. The treatment of mouse bone marrow precursor cells with mepazine strongly inhibited the RANK ligand (RANKL)-induced formation of osteoclasts, as well as the expression of several osteoclast markers, such as TRAP, cathepsin K, and calcitonin. However, RANKL induced osteoclastogenesis equally well in bone marrow cells derived from wild-type and <i>Malt1</i> knock-out mice. Furthermore, the protective effect of mepazine was not affected by MALT1 deficiency. Additionally, the absence of MALT1 did not affect RANK-induced nuclear factor κB (NF-κB) and activator protein 1 (AP-1) activation. Overall, these studies demonstrate that MALT1 is not essential for RANK-induced osteoclastogenesis, and implicate a MALT1-independent mechanism of action of mepazine that should be taken into account in future studies using this compound. |
| first_indexed | 2024-12-13T15:37:48Z |
| format | Article |
| id | doaj.art-9d245db533fa4859b36b751093580da1 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-13T15:37:48Z |
| publishDate | 2018-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-9d245db533fa4859b36b751093580da12022-12-21T23:39:57ZengMDPI AGMolecules1420-30492018-11-012312314410.3390/molecules23123144molecules23123144Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory FunctionLaura Meloni0Lynn Verstrepen1Marja Kreike2Jens Staal3Yasmine Driege4Inna S. Afonina5Rudi Beyaert6Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumUnit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumUnit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumUnit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumUnit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumUnit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumUnit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, BelgiumMucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular cysteine protease (paracaspase) that plays an integral role in innate and adaptive immunity. The phenothiazine mepazine has been shown to inhibit the proteolytic activity of MALT1 and is frequently used to study its biological role. MALT1 has recently been suggested as a therapeutic target in rheumatoid arthritis. Here, we analyzed the effect of mepazine on the receptor activator of nuclear factor κ-B (RANK)-induced osteoclastogenesis. The treatment of mouse bone marrow precursor cells with mepazine strongly inhibited the RANK ligand (RANKL)-induced formation of osteoclasts, as well as the expression of several osteoclast markers, such as TRAP, cathepsin K, and calcitonin. However, RANKL induced osteoclastogenesis equally well in bone marrow cells derived from wild-type and <i>Malt1</i> knock-out mice. Furthermore, the protective effect of mepazine was not affected by MALT1 deficiency. Additionally, the absence of MALT1 did not affect RANK-induced nuclear factor κB (NF-κB) and activator protein 1 (AP-1) activation. Overall, these studies demonstrate that MALT1 is not essential for RANK-induced osteoclastogenesis, and implicate a MALT1-independent mechanism of action of mepazine that should be taken into account in future studies using this compound.https://www.mdpi.com/1420-3049/23/12/3144osteoclastogenesismepazineMALT1RANKNF-κBphenothiazineparacaspaseosteoclast |
| spellingShingle | Laura Meloni Lynn Verstrepen Marja Kreike Jens Staal Yasmine Driege Inna S. Afonina Rudi Beyaert Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function Molecules osteoclastogenesis mepazine MALT1 RANK NF-κB phenothiazine paracaspase osteoclast |
| title | Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function |
| title_full | Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function |
| title_fullStr | Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function |
| title_full_unstemmed | Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function |
| title_short | Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function |
| title_sort | mepazine inhibits rank induced osteoclastogenesis independent of its malt1 inhibitory function |
| topic | osteoclastogenesis mepazine MALT1 RANK NF-κB phenothiazine paracaspase osteoclast |
| url | https://www.mdpi.com/1420-3049/23/12/3144 |
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