AEG-1 deletion promotes cartilage repair and modulates bone remodeling-related cytokines via TLR4/MyD88/NF-κB inhibition in ovariectomized rats with osteoporosis

Abstract

Background: Osteoporosis is a systemic skeletal disorder that can impact a variety of bones throughout the body. Astrocyte-elevated gene-1 (AEG-1) is involved in multiple pro-tumorigenic functions and participates in various inflammatory reactions. However, whether it has an impact on osteoporosis-related cartilage repair and bone remodeling remains unknown. Methods:We utilized an ovariectomy mouse model with AEG-1 deletion to investigate the role of AEG-1 in osteoporosis. The mRNA level of AEG-1 was detected by RT-PCR, bone markers, bone volume/total volume (BV/TV), trabecular bone surface/bone volume (BSA/BV) and trabecular bone thickness (Tb. Th) were detected by micro computed tomography (μCT), bone injury was observed by HE and alcian blue staining.The contents of IL-6, IL-17, iNOS and IL-10 in peripheral blood of the three groups were detected by ELISA.The expression of OSX, coi1a1, OC, TLR4, MyD88 and NF-κB were detected by Western Blot.Results: μCT revealed increased bone volume in the AEG-1 knockout (KO) ovariectomy (OVX) group compared to the wildtype (WT) OVX group 4 weeks after surgery, indicating restored bone formation after AEG-1 deletion. Flow sorting revealed that AEG-1 deletion inhibited the production of inflammatory factors. Western blot demonstrated activation of the TLR4/MyD88/NF-κB pathway after LPS exposure, which was reduced by AEG-1 deletion. AEG-1 deletion also improved lipopolysaccharide (LPS) induced adverse reactions.Conclusions: Taken together, these findings indicate that AEG-1 deletion improves cartilage repair and bone remodeling during osteoporosis, which may partly occur through the inhibition of the TLR4/MyD88/ NF-κB signaling pathway.

High-mobility group box chromosomal protein-1 deletion alleviates osteoporosis in OVX rat model via suppressing the osteoclastogenesis and inflammation

“…Besides, emerging evidence supports the involvement of TLR4/MyD88/NF-kappaB in bone remodeling [ 34 , 35 ]. For instance, inhibiting the TLR4/MyD88/NF-kappaB signaling in osteoclast precursors alleviates the progression of osteoporosis and subsequently bone loss [ 34 ].…”

“…For instance, inhibiting the TLR4/MyD88/NF-kappaB signaling in osteoclast precursors alleviates the progression of osteoporosis and subsequently bone loss [ 34 ]. Moreover, targeting TLR signaling improves cartilage repair and bone remodeling during osteoporosis [ 35 ]. Thus, the TLR signaling pathway is closely associated with osteoporosis.…”

The critical role of toll-like receptor 4 in bone remodeling of osteoporosis: from inflammation recognition to immunity

“…( 63 ) conducted a study on ovariectomized rats with osteoporosis and found that TLR4/MyD88 has the ability to regulate bone remodeling-related cytokines. The researchers observed that ovariectomy led to the activation of the TLR4/MyD88/NF-κB pathway, but this effect was nullified when HMGB-1 was knocked down ( 58 ), miR-1906 was mimicked ( 61 ), or AEG-1 was deleted ( 63 ). Inhibition of the TLR4/MyD88/NF-κB pathway demonstrated positive outcomes such as mitigating bone histopathological damage, reducing bone loss, and promoting osteogenesis.…”

“…As shown in Figure 1 with the flow diagram, thirty studies were finally included. Among them, six included studies (39,(41)(42)(43)(44)(45) provided the clinical data from osteoporosis patients (Table 1), 17 studies (12,37,38,40,(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58) reported the molecular mechanisms underlying the role of TLR4 in osteoporosis (Table 2), and seven studies (59)(60)(61)(62)(63)(64)(65) provided the data of specific treatments-targeted TLR4 for osteoporosis (Table 3). The key information of the 30 eligible studies included the study object, disease modeling method, the status of TLR4, effect on osteoblast or osteoclast, associated genes or pathways, and the main findings of the independent study.…”

“…Zhang et al ( 63) conducted a study on ovariectomized rats with osteoporosis and found that TLR4/ MyD88 has the ability to regulate bone remodeling-related cytokines. The researchers observed that ovariectomy led to the activation of the TLR4/MyD88/NF-kB pathway, but this effect was nullified when HMGB-1 was knocked down (58), miR-1906 was mimicked (61), or AEG-1 was deleted (63). Inhibition of the TLR4/ MyD88/NF-kB pathway demonstrated positive outcomes such as mitigating bone histopathological damage, reducing bone loss, and promoting osteogenesis.…”