Diabetes and osteoporosis: a two-sample mendelian randomization study.

BACKGROUND: The effects on bone mineral density (BMD)/fracture between type 1 (T1D) and type 2 (T2D) diabetes are unknown. Therefore, we aimed to investigate the causal relationship between the two types of diabetes and BMD/fracture using a Mendelian randomization (MR) design. METHODS: A two-sample MR study was conducted to examine the causal relationship between diabetes and BMD/fracture, with three phenotypes (T1D, T2D, and glycosylated hemoglobin [HbA1c]) of diabetes as exposures and five phenotypes (femoral neck BMD [FN-BMD], lumbar spine BMD [LS-BMD], heel-BMD, total body BMD [TB-BMD], and fracture) as outcomes, combining MR-Egger, weighted median, simple mode, and inverse variance weighted (IVW) sensitivity assessments. Additionally, horizontal pleiotropy was evaluated and corrected using the residual sum and outlier approaches. RESULTS: The IVW method showed that genetically predicted T1D was negatively associated with TB-BMD (ß = -0.018, 95% CI: -0.030, -0.006), while T2D was positively associated with FN-BMD (ß = 0.033, 95% CI: 0.003, 0.062), heel-BMD (ß = 0.018, 95% CI: 0.006, 0.031), and TB-BMD (ß = 0.050, 95% CI: 0.022, 0.079). Further, HbA1c was not associated with the five outcomes (ß ranged from - 0.012 to 0.075). CONCLUSIONS: Our results showed that T1D and T2D have different effects on BMD at the genetic level. BMD decreased in patients with T1D and increased in those with T2D. These findings highlight the complex interplay between diabetes and bone health, suggesting potential age-specific effects and genetic influences. To better understand the mechanisms of bone metabolism in patients with diabetes, further longitudinal studies are required to explain BMD changes in different types of diabetes.

MicroRNA-18a regulates the Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) of osteoblasts induced by tumor necrosis factor-α via hypoxia-inducible factor-1α.

BACKGROUND: Tumor necrosis factor-α (TNF-α) is involved in inflammatory responses and promotes cell death and the inhibition of osteogenic differentiation. MicroRNA (miRNA) plays a crucial role in the infected bone diseases, however, the biological role of miRNAs in inflammation-induced impaired osteogenic differentiation remains unclear. This study aimed to explore the role of miRNA-18a-5p (miR-18a) in regulating PANoptosis and osteogenic differentiation in an inflammatory environment via hypoxia-inducible factor-1α (HIF1-α). METHODS: The expression of miR-18a in MC3T3-E1 cells was analyzed using quantitative reverse transcription-polymerase chain reaction in an inflammatory environment induced by TNF-α. The expression of HIF1-α and NLRP3 in LV-miR-18a or sh-miR-18a cells was analyzed using western blotting. Fluorescence imaging for cell death, flow cytometry, and alkaline phosphatase activity analysis were used to analyze the role of miR-18a in TNF-α-induced PANoptosis and the inhibition of osteogenic differentiation. An animal model of infectious bone defect was established to validate the regulatory role of miR-18a in an inflammatory environment. RESULTS: The expression of miRNA-18a in the MC3T3-E1 cell line was significantly lower under TNF-α stimulation than in the normal environment. miR-18a significantly inhibited the expression of HIF1-α and NLRP3, and inhibition of HIF1-α expression further inhibited NLRP3 expression. Furthermore, inhibition of miR-18a expression promoted the TNF-α-induced PANoptosis and inhibition of osteogenic differentiation, whereas miR-18a overexpression and the inhibition of both HIF1-α and NLRP3 reduced the effects of TNF-α. These findings are consistent with those of the animal experiments. CONCLUSION: miRNA-18a negatively affects HIF1-α/NLRP3 expression, inhibits inflammation-induced PANoptosis, and impairs osteogenic differentiation. Thus, it is a potential therapeutic candidate for developing anti-inflammatory strategies for infected bone diseases.

Chronic osteomyelitis risk is associated with NLRP3 gene rs10754558 polymorphism in a Chinese Han Population.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the nucleotide-binding domain leucine-rich repeat protein-3 (NLRP3) gene are reported to be linked to many inflammatory disorders. However, uncertainty persists over the associations between these SNPs and susceptibilities to chronic osteomyelitis (COM). This study aimed to investigate potential relationships between NLRP3 gene SNPs and the risks of developing COM in a Chinese Han cohort. METHODS: The four tag SNPs of the NLRP3 gene were genotyped in a total of 428 COM patients and 368 healthy controlsusing the SNapShot technique. The genotype distribution, mutant allele frequency, and the four genetic models (dominant, recessive, homozygous, and heterozygous) of the four SNPs were compared between the two groups. RESULTS: A significant association was found between rs10754558 polymorphism and the probability of COM occurence by the heterozygous model (P = 0.037, odds ratio [OR] = 1.541, 95% confidence interval [CI] = 1.025-2.319), indicating that rs10754558 may be associated with a higher risk of developing COM.In addition, possible relationship was found between rs7525979 polymorphism and the risk of COM development by the outcomes of homozygous (P = 0.073, OR = 0.453, 95% CI = 0.187-1.097) and recessive (P = 0.093, OR = 0.478, 95% CI = 0.198-1.151) models, though no statistical differences were obtained. CONCLUSIONS: Outcomes of the present study showed, for the first time, that rs10754558 polymorphism of the NLRP3 gene may increase the risk of COM development in this Chinese Han population, with genotype CG as a risk factor. Nonetheless, this conclusion requires verification from further studies with a larger sample size.

Posttraumatic Osteomyelitis Risks Associated with NLRP3 Gene Polymorphisms in the Chinese Population.

The purpose of this case-control study was to examine possible links between NLRP3 gene polymorphisms and the risk of developing posttraumatic osteomyelitis (PTOM) in the Chinese population. A total of 306 patients with PTOM and 368 normal controls were genotyped for NLRP3 (rs35829419, rs10754558, rs7525979, rs4612666), ELP2 (rs1785929, rs1789547, rs1785928, rs12185396, rs681757, rs8299, rs2032206, rs559289), STAT3 (rs4796793, rs744166, rs1026916, rs2293152, rs1053004), CASP1 (rs501192, rs580253, rs556205, rs530537), NFKBIA (rs696), NFKB1 (rs4648068), CARD8 (rs204321), and CD14 (rs2569190) using the genotyping technique SNaPshot. The genotype distributions of NLRP3 gene rs10754558 (p = 0.047) and rs7525979 (p = 0.048) significantly differed between the patients and the healthy controls. Additionally, heterozygous models indicated a significant association between NLRP3 rs10754558 and the likelihood of developing PTOM (OR = 1.600, p = 0.039), as did recessive and homozygous models of NLRP3 rs7525979 (OR = 0.248, p = 0.019 and 0.239, p = 0.016, respectively). Collectively, our findings suggest that, in the Chinese population, the risk of developing PTOM was increased by the association between NLRP3 rs10754558 and rs7525979. Therefore, our findings may provide novel insights and guidance in the prevention and development of PTOM.

Tibial cortex transverse transport potentiates diabetic wound healing via activation of SDF-1/CXCR4 signaling.

Background: The current treatments for diabetic foot ulcers have disadvantages of slow action and numerous complications. Tibial cortex transverse transport (TTT) surgery is an extension of the Ilizarov technique used to treat diabetic foot ulcers, and can shorten the repair time of diabetic foot ulcers. This study assessed the TTT technique for its effectiveness in healing diabetic foot ulcer skin lesions and its related molecular mechanisms. Methods: Diabetic rat models were established by injecting healthy Sprague-Dawley rats with streptozotocin (STZ). The effects of TTT surgery on the model rats were assessed by recording changes in body weight, analyzing skin wound pictures, and performing H&E staining to assess the recovery of wounded skin. The numbers of endothelial progenitor cells (EPCs) in peripheral blood were analyzed by flow cytometry, and levels of CXCR4 and SDF-1 expression were qualitatively analyzed by immunofluorescence, immunohistochemistry, qRT-PCR, and western blotting. Results: Both the histological results and foot wound pictures indicated that TTT promoted diabetic wound healing. Flow cytometry results showed that TTT increased the numbers of EPCs in peripheral blood as determined by CD34 and CD133 expression. In addition, activation of the SDF-1/CXCR4 signaling pathway and an accumulation of EPCs were observed in skin ulcers sites after TTT surgery. Finally, the levels of SDF-1 and CXCR4 mRNA and protein expression in the TTT group were higher than those in a blank or fixator group. Conclusion: TTT promoted skin wound healing in diabetic foot ulcers possibly by activating the SDF-1/CXCR4 signaling pathway.

Osteoporosis and osteoarthritis: a bi-directional Mendelian randomization study.

OBJECTIVE: To investigate the causal relationship between low bone mineral density (BMD) and osteoarthritis (OA) using Mendelian randomization (MR) design. METHODS: Two-sample bi-directional MR analyses were performed using summary-level information on OA traits from UK Biobank and arcOGEN. Sensitivity analyses including MR-Egger, simple median, weighted median, MR pleiotropy residual sum, and outlier approaches were utilized in conjunction with inverse variance weighting (IVW). Gene ontology (GO) enrichment analyses and expression quantitative trait locus (eQTL) colocalization analyses were used to investigate the potential mechanism and shared genes between osteoporosis (OP) and OA. RESULTS: The IVW method revealed that genetically predicted low femoral neck BMD was significantly linked with hip (ß = 0.105, 95% CI: 0.023-0.188) and knee OA (ß = 0.117, 95% CI: 0.049-0.184), but not with other site-specific OA. Genetically predicted low lumber spine BMD was significantly associated with OA at any sites (ß = 0.048, 95% CI: 0.011-0.085), knee OA (ß = 0.101, 95% CI: 0.045-0.156), and hip OA (ß = 0.150, 95% CI: 0.077-0.224). Only hip OA was significantly linked with genetically predicted reduced total bone BMD (ß = 0.092, 95% CI: 0.010-0.174). In the reverse MR analyses, no evidence for a causal effect of OA on BMD was found. GO enrichment analysis and eQTL analysis illustrated that DDN and SMAD-3 were the most prominent co-located genes. CONCLUSIONS: These findings suggested that OP may be causally linked to an increased risk of OA, indicating that measures to raise BMD may be effective in preventing OA. More research is required to determine the underlying processes via which OP causes OA.

A cell adhesion-promoting multi-network 3D printing bio-ink based on natural polysaccharide hydrogel.

Due to its high biosafety, gellan gum (GG) hydrogel, a naturally occurring polysaccharide released by microorganisms, is frequently utilized in food and pharmaceuticals. In recent years, like GG, natural polysaccharide-based hydrogels have become increasingly popular in 3D-printed biomedical engineering because of their simplicity of processing, considerable shear thinning characteristic, and minimal pH dependence. To mitigate the negative effects of the GG's high biological inertia, poor cell adhesion, single cross-linked network, and high brittleness. Mesoporous silica nanospheres (MMSN) and Aldehyde-based methacrylated hyaluronic acid (AHAMA) were combined to sulfhydrated GG (TGG) to create a multi-network AHAMA/TGG/MMSN hydrogel in this study. For this composite hydrogel system, the multi-component offers several crosslinking networks: the double bond in AHAMA can be photocrosslinked by activating the photoinitiator, aldehyde groups on its side chain can create Schiff base bonds with MMSN, while TGG can self-curing at room temperature. The AHAMA/TGG/MMSN hydrogel, with a mass ratio of 2:6:1, exhibits good cell adhesion, high strength and elasticity, and great printability. We believe that this innovative multi-network hydrogel has potential uses in tissue regeneration and biomedical engineering.