Causal relationship between bone mineral density and intervertebral disc degeneration: a univariate and multivariable mendelian randomization study.

BACKGROUND: Although previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality. OBJECTIVES: This Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD). METHODS: Summary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation. RESULTS: In the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E - 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD. CONCLUSIONS: The findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.

Research on Synchronous Control of Active Disturbance Rejection Position of Multiple Hydraulic Cylinders of Digging-Anchor-Support Robot.

In order to solve the problems of nonlinearity, uncertainty and coupling of multi-hydraulic cylinder group platform of a digging-anchor-support robot, as well as the lack of synchronization control accuracy of hydraulic synchronous motors, an improved Automatic Disturbance Rejection Controller-Improved Particle Swarm Optimization (ADRC-IPSO) position synchronization control method is proposed. The mathematical model of a multi-hydraulic cylinder group platform of a digging-anchor-support robot is established, the compression factor is used to replace the inertia weight, and the traditional Particle Swarm Optimization (PSO) algorithm is improved by using the genetic algorithm theory to improve the optimization range and convergence rate of the algorithm, and the parameters of the Active Disturbance Rejection Controller (ADRC) were adjusted online. The simulation results verify the effectiveness of the improved ADRC-IPSO control method. The experimental results show that, compared with the traditional ADRC, ADRC-PSO and PID controller, the improved ADRC-IPSO has better position tracking performance and shorter adjusting time, and its step signal synchronization error is controlled within 5.0 mm, and the adjusting time is less than 2.55 s, indicating that the designed controller has better synchronization control effect.

Seipin differentially regulates lipogenesis and adipogenesis through a conserved core sequence and an evolutionarily acquired C-terminus.

Homozygous mutations in BSCL2 (Berardinelli-Seip congenital lipodystrophy)/seipin cause CGL2 (congenital generalized lipodystrophy type 2). Recent data suggest that seipin regulates LD (lipid droplet) dynamics and adipocyte differentiation, but whether these roles are mechanistically linked remains unclear. To understand how seipin regulates these processes, we investigated the evolutionary changes of seipin orthologues, and studied individual domains in regulating lipid accumulation in non-adipocytes and adipocytes. Mammalian seipins comprise at least two distinct functional domains, a conserved core sequence and an evolutionarily acquired C-terminus. Despite its requirement for adipocyte formation, seipin overexpression inhibited oleate-induced LD formation and accumulation in nonadipocytes, which was mediated by the core sequence. In contrast, seipin overexpression did not inhibit LD accumulation during adipocyte differentiation or the adipogenic process in 3T3-L1 cells. However, adipogenesis and LD accumulation were impaired in 3T3-L1 cells expressing a seipin mutant lacking the C-terminus. Furthermore, expression of the same mutant without the C-terminus failed to rescue the adipogenic defects in seipin-knockdown cells, demonstrating the importance of the C-terminus for seipin's function in adipocyte development. We propose that seipin is involved in lipid homoeostasis by restricting lipogenesis and LD accumulation in non-adipocytes, while promoting adipogenesis to accommodate excess energy storage.

Regulation of adipogenesis by cytoskeleton remodelling is facilitated by acetyltransferase MEC-17-dependent acetylation of α-tubulin.

Cytoskeleton remodelling is a prerequisite step for the morphological transition from preadipocytes to mature adipocytes. Although microtubules play a pivotal role in organizing cellular structure, regulation of microtubule dynamics during adipogenesis remains unclear. In the present paper we show that acetylation of α-tubulin is up-regulated during adipogenesis, and adipocyte development is dependent on α-tubulin acetylation, as expression of an acetylation-resistant α-tubulin mutant significantly inhibits adipogenesis. Moreover, acetylation of α-tubulin is under the control of the acetyltransferase MEC-17 and deacetylases SIRT2 (Sirtuin 2) and HDAC6 (histone deacetylase 6). Adipocyte development is inhibited in MEC-17-knockdown cells, but enhanced in MEC-17-overexpressing cells. Finally, we show that katanin, a microtubule-severing protein with enhanced activity on acetylated α-tubulin, is actively involved in adipogenesis. We propose that co-ordinated up-regulation of α-tubulin acetylation initiates cytoskeleton remodelling by promoting α-tubulin severing by katanin which, in turn, allows expansion of lipid droplets and accelerates the morphological transition toward mature adipocytes.