Sdccag3 Promotes Implant Osseointegration during Experimental Hyperlipidemia

Abstract

<jats:p> Hyperlipidemia adversely affects bone metabolism, often resulting in compromised osseointegration and implant loss. In addition, genetic networks associated with osseointegration have been proposed. Serologically defined colon cancer antigen 3 (Sdccag3) is a novel endosomal protein that functions in actin cytoskeleton remodeling, protein trafficking and secretion, cytokinesis, and apoptosis, but its roles in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and in implant osseointegration under hyperlipidemic conditions have not been uncovered. Here, we performed microarray and RNA sequencing analysis to determine the differential expression of the Sdccag3 gene and related noncoding RNAs (ncRNAs) and to assess the long noncoding RNA (lncRNA) MSTRG.97162.4-miR-193a-3p-Sdccag3 coexpression network in bone tissues within the region 0.5 mm around implants in hyperlipidemic rats. In this experiment, we found that Sdccag3 and the previously uncharacterized lncRNA-MSTRG.97162.4 were downregulated during hyperlipidemia, while miR-193a-3p was upregulated. Sdccag3 overexpression increased new trabecular formation, the bone volume/total volume (BV/TV) (1.24-fold), and bone-implant combination ratio (BIC%) (1.26-fold). An RNA pulldown experiment revealed that Sdccag3 protein targeted lncRNA-MSTRG.97162.4 nucleotides 361 to 389. In addition, lncRNA-MSTRG.97162.4 overexpression significantly enhanced Sdccag3 (2.78-fold) expression and increased BV/TV (1.45-fold) and BIC% (1.07-fold) at the bone-implant interface. Taken together, these findings indicate that Sdccag3 overexpression enhances implant osseointegration under hyperlipidemic conditions by binding to lncRNA-MSTRG.97162.4. Furthermore, miR-193a-3p overexpression inhibited lncRNA-MSTRG.97162.4 (0.63-fold) and Sdccag3 (0.88-fold) expression and induced poor implant osseointegration (BV/TV, 0.86-fold; BIC%, 0.82-fold), while miR-193a-3p downregulation produced the opposite results (lncRNA-MSTRG.97162.4, 10.69-fold; Sdccag3, 6.96-fold; BV/TV, 1.20-fold; BIC%, 1.26-fold). Therefore, our findings show that Sdccag3 promotes implant osseointegration, and its related lncRNA-MSTRG.97162.4 and miR-193a-3p play an important role in osseointegration during hyperlipidemia, which might be a promising therapeutic target for improving dental implantation success rates. </jats:p>

Hyperlipidemia impairs bone regeneration of closed bone defects and tooth extraction wounds in mice

“…After fed the animals with an atherogenic HFD, we found that both serum TC level and serum LDL‐c level in the HFD‐fed mice were increased by approximately 2–3 folds when compared with the corresponding control animals fed with the standard diet. Consistent with previous findings showing that hyperlipidemia adversely affects bone metabolism, 12–15 we observed delayed bone regeneration and inhibited bone formation in the closed mandibular bone defect region of animals fed with the HFD when compared with that of animals fed with the standard diet. Using two hyperlipidemic animal models, it has been reported that a hyperlipidemic microenvironment significantly blunted parathyroid hormone (PTH)‐induced bone anabolism 25 .…”

“…When fed with a cholesterol‐containing HFD for 12 weeks, Apoe−/− mice, a hyperlipidemic mouse model developed on the C57BL/6 genetic background, showed an approximately 8‐fold increase in TC level, and displayed decreased cortical bone volume and inhibited bone formation 12 . Using mouse and rat models, hyperlipidemia was proved to adversely affect bone metabolism and result in compromised osseointegration, eventually leading to implant loss 13 . In addition, HFD was reported to result in larger lesions of apical periodontitis with a more severe inflammatory infiltrate or significantly accelerate the progression of periodontitis 14,15 …”

Hyperlipidemia Impairs Osseointegration via the ROS/Wnt/β-Catenin Pathway

“…This is consistent with other reported findings. For example, H. Ren and Krishanthi Gunaratnam confirmed in 2 separate studies that high-fat stimulation could inhibit the osteogenic differentiation of rat bone marrow stem cells and human osteoblasts (Gunaratnam et al 2014; Ren et al 2020). Finally, and crucially, the high-fat stimulation impaired cell skeleton arrangement, morphology, and migration and also increased the accumulation of intracellular lipids.…”

“…Besides the inconsistent findings in clinical trials, some controversies and limitations still exist in basic research. It has been reported that a high-fat diet (HFD) in Wistar rats (Ren et al 2020), C57BL/6J mice (Keuroghlian et al 2015), and New Zealand rabbits (Tekin and Toker 2019) resulted in compromised osseointegration, whereas Dundar and Yaman (2016) reported that a HFD did not decrease the bone-implant connection rate in rabbit tibias. These inconsistent findings in clinical trials, as well as controversies in basic research, show the urgent need for more comprehensive and systematical studies on the effects of hyperlipidemia on implant osseointegration.…”

Effects of Hyperlipidemia on Osseointegration of Dental Implants and Its Strategies

“…Some researchers have injected enhancers or inhibitors locally by genetic engineering. Ren et al used microarray analysis to study the effects of hyperlipidemia on osseointegration and found that applying Sdccag3-enhancer, lncRNA-MSTRG.97162.4-enhancer and miR-193a-3p-inhibitor could boost bone formation of BMSC in vitro and improve osseointegration in vivo [60]. MiR-29a-3p-enhancer was also beneficial in implant osseointegration [61].…”