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

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 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-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 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.

Dietary Resistant Starch Alleviates Escherichia Coli-induced Bone Loss in Meat Ducks by Promoting Short-chain Fatty Acid Production and Inhibiting Malt1/NF-κB Inflammasome Activation

“…Deletion of Malt1 in mouse T cells (Malt1 TcellKO ) protects against development of autoimmune arthritis but leads to spontaneous osteoporosis [44]. Malt1 de cient (Malt1 KO ) mice were also noticed to develop an osteoporotic phenotype with increased osteoclastogenesis in vivo [45]. It appears to deem that knockout Malt1 brought about inferior bone quality, independent from a direct role of Malt1 in in ammation mediated osteoclastogenesis, which is completely contrary to our observations.…”

Blood MALT1, Th1, and Th17 cells are dysregulated, inter‐correlated, and correlated with disease activity in rheumatoid arthritis patients; meanwhile, MALT1 decline during therapy relates to treatment outcome

“… 23 , 34 Our study found that MALT1 expression, Th1, and Th17 cells were all higher in RA patients than in HCs; additionally, MALT1 was positively associated with Th1 and Th17 cells. The possible reasons might be that (1) as what was mentioned above, MALT1 would cause the occurrence of inflammatory via trigging many signaling pathway; meanwhile, RA was characterized by excessive inflammation 34 , 35 ; hence, MALT1 was increased in RA patients than in HCs. (2) MALT1 trigged the activation of T cells and promoted the differentiation of CD4 + T cells into Th1 and Th17 cells.…”

MALT1 positively relates to Th17 cells, inflammation/activity degree, and its decrement along with treatment reflects TNF inhibitor response in ankylosing spondylitis patients

“…10,19 (2) MALT1 is excessively expressed and activated in osteoclasts, who are highly proliferated in AS pathology; therefore, MALT1 is consequently overexpressed in AS patients. 12,13 Some previous studies reveal that MALT1 maintains the homeostasis of CD4 + T cells and represses the differentiation of Th1 and Th17 cells in vitro and in vivo, whereas its correlation with Th cells in AS patients has never been explored. [9][10][11] Our study found that MALT1 expression was positively correlated with Th17 cells in AS patients.…”

“…[9][10][11] Additionally, MALT1 is excessively expressed in osteoclasts; meanwhile, inhibiting MALT1 suppresses the differentiation of monocytes into osteoclasts in mice. 12,13 What is more, a preclinical study in the field of AS discloses that inhibiting MALT1 represses the level of inflammation via regulating NF-κB signaling. 14 (e) had liver, kidney, heart, or respiration dysfunction.…”