Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation and bone destruction as the result of increased numbers and activity of osteoclasts. RA is... Show moreRheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation and bone destruction as the result of increased numbers and activity of osteoclasts. RA is often associated with metabolic syndrome, whereby elevated levels of LDL are oxidized into oxLDL, which might affect osteoclastogenesis. In this study, we induced antigen-induced arthritis (AIA) in Apoe(-/-) mice, which spontaneously develop high LDL levels, to investigate the effects of high LDL/oxLDL levels on osteoclast differentiation and bone destruction. Whereas basal levels of bone resorption were comparable between naive WT and Apoe(-/-) mice, induction of AIA resulted in a significant reduction of bone destruction in Apoe(-/-) mice as compared to WT controls. In line with that, the TRAP(+) area on the cortical bone was significantly decreased. The absence of Apoe did affect neither the numbers of CD11b(+) Ly6C(high) and CD11b(-)/Ly6C(high)osteoclast precursors (OCPs) in the BM of naive mice nor their in vitro osteoclastogenic potential as indicated by comparable mRNA expression of osteoclast markers. Addition of oxLDL, but not LDL, to pre-osteoclasts from day 3 and mature osteoclasts from day 6 of osteoclastogenesis strongly reduced the number of TRAP(+) osteoclasts and their resorptive capacity. This coincided with a decreased expression of various osteoclast markers. Interestingly, oxLDL significantly lowered the expression of osteoclast-associated receptor (Oscar) and the DNAX adaptor protein-12 encoding gene Tyrobp, which regulate the immunoreceptor tyrosine-based activation motif (ITAM) co-stimulation pathway that is strongly involved in osteoclastogenesis. Collectively, our findings suggest that under inflammatory conditions in the joint, high LDL levels lessen bone destruction during AIA, probably by formation of oxLDL that inhibits osteoclast formation and activity through modulation of the ITAM-signaling. Show less
Ascone, G.; Di Ceglie, I.; Walgreen, B.; Sloetjes, A.W.; Lindhout, E.; Bot, I.; ... ; Lent, P.L.E.M. van 2019
Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation andbone destruction as the result of increased numbers and activity of osteoclasts. RA is... Show moreRheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation andbone destruction as the result of increased numbers and activity of osteoclasts. RA is often associated withmetabolic syndrome, whereby elevated levels of LDL are oxidized into oxLDL, which might affect osteoclastogenesis.In this study, we induced antigen-induced arthritis (AIA) in Apoe−/− mice, which spontaneously develophigh LDL levels, to investigate the effects of high LDL/oxLDL levels on osteoclast differentiation and bonedestruction. Whereas basal levels of bone resorption were comparable between naive WT and Apoe−/− mice,induction of AIA resulted in a significant reduction of bone destruction in Apoe−/− mice as compared to WTcontrols. In line with that, the TRAP+ area on the cortical bone was significantly decreased. The absence of Apoedid affect neither the numbers of CD11b+Ly6Chigh and CD11b−/Ly6Chigh osteoclast precursors (OCPs) in the BMof naïve mice nor their in vitro osteoclastogenic potential as indicated by comparable mRNA expression ofosteoclast markers. Addition of oxLDL, but not LDL, to pre-osteoclasts from day 3 and mature osteoclasts fromday 6 of osteoclastogenesis strongly reduced the number of TRAP+ osteoclasts and their resorptive capacity. Thiscoincided with a decreased expression of various osteoclast markers. Interestingly, oxLDL significantly loweredthe expression of osteoclast-associated receptor (Oscar) and the DNAX adaptor protein-12 encoding gene Tyrobp,which regulate the immunoreceptor tyrosine-based activation motif (ITAM) co-stimulation pathway that isstrongly involved in osteoclastogenesis. Collectively, our findings suggest that under inflammatory conditions inthe joint, high LDL levels lessen bone destruction during AIA, probably by formation of oxLDL that inhibitsosteoclast formation and activity through modulation of the ITAM-signaling. Show less
