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Mepazine inhibits RANK-induced osteoclastogenesis independent of its MALT1 inhibitory function

Laura Meloni (UGent) , Lynn Verstrepen (UGent) , Marja Kreike (UGent) , Jens Staal (UGent) , Yasmine Driege (UGent) , Inna Afonina (UGent) and Rudi Beyaert (UGent)
(2018) MOLECULES. 23(12).
Author
Organization
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
osteoclastogenesis, mepazine, MALT1, RANK, NF-B, phenothiazine, paracaspase, osteoclast, KAPPA-B ACTIVATION, T-CELL, PHENOTHIAZINE-DERIVATIVES, BONE-RESORPTION, CMV PROMOTER, RECEPTOR, CHLORPROMAZINE, DIFFERENTIATION, PROTEIN, DEFICIENCY

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Citation

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MLA
Meloni, Laura et al. “Mepazine Inhibits RANK-induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function.” MOLECULES 23.12 (2018): n. pag. Print.
APA
Meloni, L., Verstrepen, L., Kreike, M., Staal, J., Driege, Y., Afonina, I., & Beyaert, R. (2018). Mepazine inhibits RANK-induced osteoclastogenesis independent of its MALT1 inhibitory function. MOLECULES, 23(12).
Chicago author-date
Meloni, Laura, Lynn Verstrepen, Marja Kreike, Jens Staal, Yasmine Driege, Inna Afonina, and Rudi Beyaert. 2018. “Mepazine Inhibits RANK-induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function.” Molecules 23 (12).
Chicago author-date (all authors)
Meloni, Laura, Lynn Verstrepen, Marja Kreike, Jens Staal, Yasmine Driege, Inna Afonina, and Rudi Beyaert. 2018. “Mepazine Inhibits RANK-induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function.” Molecules 23 (12).
Vancouver
1.
Meloni L, Verstrepen L, Kreike M, Staal J, Driege Y, Afonina I, et al. Mepazine inhibits RANK-induced osteoclastogenesis independent of its MALT1 inhibitory function. MOLECULES. 2018;23(12).
IEEE
[1]
L. Meloni et al., “Mepazine inhibits RANK-induced osteoclastogenesis independent of its MALT1 inhibitory function,” MOLECULES, vol. 23, no. 12, 2018.
@article{8587323,
  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.},
  articleno    = {3144},
  author       = {Meloni, Laura and Verstrepen, Lynn and Kreike, Marja and Staal, Jens and Driege, Yasmine and Afonina, Inna and Beyaert, Rudi},
  issn         = {1420-3049},
  journal      = {MOLECULES},
  keywords     = {osteoclastogenesis,mepazine,MALT1,RANK,NF-B,phenothiazine,paracaspase,osteoclast,KAPPA-B ACTIVATION,T-CELL,PHENOTHIAZINE-DERIVATIVES,BONE-RESORPTION,CMV PROMOTER,RECEPTOR,CHLORPROMAZINE,DIFFERENTIATION,PROTEIN,DEFICIENCY},
  language     = {eng},
  number       = {12},
  pages        = {13},
  title        = {Mepazine inhibits RANK-induced osteoclastogenesis independent of its MALT1 inhibitory function},
  url          = {http://dx.doi.org/10.3390/molecules23123144},
  volume       = {23},
  year         = {2018},
}

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