Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency

Mahdis Monajemi, Shera Fisk, Yvonne C. F. Pang, Jessica Leung, Susan C. Menzies, Rym Ben-Othman, Bing Cai, Tobias R. Kollmann, Jacob Rozmus, Laura M. Sly

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Abstract

This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient M phi s, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-kappa B ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1(-/-)) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in M phi s induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.

Original languageEnglish
Number of pages15
JournalJournal of Leukocyte Biology
DOIs
Publication statusE-pub ahead of print - 16 Jul 2019

Cite this

Monajemi, Mahdis ; Fisk, Shera ; Pang, Yvonne C. F. ; Leung, Jessica ; Menzies, Susan C. ; Ben-Othman, Rym ; Cai, Bing ; Kollmann, Tobias R. ; Rozmus, Jacob ; Sly, Laura M. / Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency. In: Journal of Leukocyte Biology. 2019.
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abstract = "This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient M phi s, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-kappa B ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1(-/-)) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in M phi s induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.",
keywords = "combined immunodeficiency, macrophage colony-stimulating factor, macrophages, Malt1, osteoclasts, osteoporosis, osteoprotegerin, NF-KAPPA-B, COLONY-STIMULATING FACTOR, BETA-GLUCAN RECEPTOR, T-CELL, COMBINED IMMUNODEFICIENCY, PARACASPASE MALT1, PHARMACOLOGICAL INHIBITION, SIGNALING PATHWAY, PROTECTS MICE, DIFFERENTIATION",
author = "Mahdis Monajemi and Shera Fisk and Pang, {Yvonne C. F.} and Jessica Leung and Menzies, {Susan C.} and Rym Ben-Othman and Bing Cai and Kollmann, {Tobias R.} and Jacob Rozmus and Sly, {Laura M.}",
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Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency. / Monajemi, Mahdis; Fisk, Shera; Pang, Yvonne C. F.; Leung, Jessica; Menzies, Susan C.; Ben-Othman, Rym; Cai, Bing; Kollmann, Tobias R.; Rozmus, Jacob; Sly, Laura M.

In: Journal of Leukocyte Biology, 16.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency

AU - Monajemi, Mahdis

AU - Fisk, Shera

AU - Pang, Yvonne C. F.

AU - Leung, Jessica

AU - Menzies, Susan C.

AU - Ben-Othman, Rym

AU - Cai, Bing

AU - Kollmann, Tobias R.

AU - Rozmus, Jacob

AU - Sly, Laura M.

PY - 2019/7/16

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N2 - This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient M phi s, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-kappa B ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1(-/-)) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in M phi s induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.

AB - This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient M phi s, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-kappa B ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1(-/-)) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in M phi s induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.

KW - combined immunodeficiency

KW - macrophage colony-stimulating factor

KW - macrophages

KW - Malt1

KW - osteoclasts

KW - osteoporosis

KW - osteoprotegerin

KW - NF-KAPPA-B

KW - COLONY-STIMULATING FACTOR

KW - BETA-GLUCAN RECEPTOR

KW - T-CELL

KW - COMBINED IMMUNODEFICIENCY

KW - PARACASPASE MALT1

KW - PHARMACOLOGICAL INHIBITION

KW - SIGNALING PATHWAY

KW - PROTECTS MICE

KW - DIFFERENTIATION

U2 - 10.1002/JLB.5VMA0219-054R

DO - 10.1002/JLB.5VMA0219-054R

M3 - Article

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

ER -