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Open AccessArticle

Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function

1
Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
2
Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(12), 3144; https://doi.org/10.3390/molecules23123144
Received: 5 November 2018 / Revised: 23 November 2018 / Accepted: 27 November 2018 / Published: 30 November 2018
(This article belongs to the Section Medicinal Chemistry)
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 Malt1 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. View Full-Text
Keywords: osteoclastogenesis; mepazine; MALT1; RANK; NF-κB; phenothiazine; paracaspase; osteoclast osteoclastogenesis; mepazine; MALT1; RANK; NF-κB; phenothiazine; paracaspase; osteoclast
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MDPI and ACS Style

Meloni, L.; Verstrepen, L.; Kreike, M.; Staal, J.; Driege, Y.; Afonina, I.S.; Beyaert, R. Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function. Molecules 2018, 23, 3144.

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