2. Academic Validation
  3. Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function

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

  • Molecules. 2018 Nov 30;23(12):3144. doi: 10.3390/molecules23123144.
Laura Meloni 1 2,  Lynn Verstrepen 3 4,  Marja Kreike 5 6,  Jens Staal 7 8,  Yasmine Driege 9 10,  Inna S Afonina 11 12,  Rudi Beyaert 13 14
Affiliations

Affiliations

  • 1 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. laurameloni86@gmail.com.
  • 2 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. laurameloni86@gmail.com.
  • 3 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. lynn.verstrepen@prodigest.eu.
  • 4 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. lynn.verstrepen@prodigest.eu.
  • 5 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. marja.kreike@irc.vib-ugent.be.
  • 6 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. marja.kreike@irc.vib-ugent.be.
  • 7 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. Jens.Staal@irc.vib-UGent.be.
  • 8 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Jens.Staal@irc.vib-UGent.be.
  • 9 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. yasmine.driege@irc.vib-ugent.be.
  • 10 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. yasmine.driege@irc.vib-ugent.be.
  • 11 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. inna.afonina@irc.vib-ugent.be.
  • 12 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. inna.afonina@irc.vib-ugent.be.
  • 13 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium. Rudi.Beyaert@irc.vib-UGent.be.
  • 14 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Rudi.Beyaert@irc.vib-UGent.be.
PMID: 30513612 DOI: 10.3390/molecules23123144
Abstract

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.

Keywords

MALT1; NF-κB; RANK; mepazine; osteoclast; osteoclastogenesis; paracaspase; phenothiazine.

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