SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.

Nucleus pulposus (NP) cell function-loss is one main contributor during intervertebral disc degeneration (IDD) progression. Both mitochondria and endoplasmic reticulum (ER) play vital roles in sustaining NP cell homeostasis, while the precise function of ER-mitochondria tethering and cross talk in IDD remain to be clarified. Here, we demonstrated that a notable disruption of mitochondria-associated ER membrane (MAM) was identified in degenerated discs and TBHP-induced NP cells, accompanied by mitochondrial Zn2+ overload and NP cell senescence. Importantly, experimental coupling of MAM contacts by MFN2, a critical regulator of MAM formation, could enhance NLRX1-SLC39A7 complex formation and mitochondrial Zn2+ homeostasis. Further using the sequencing data from TBHP-induced degenerative model of NP cells, combining the reported MAM proteomes, we demonstrated that SYNJ2BP loss was one critical pathological characteristic of NP cell senescence and IDD progression, which showed close relationship with MAM disruption. Overexpression of SYNJ2BP could facilitate MAM contact organization and NLRX1-SLC39A7 complex formation, thus promoted mitochondrial Zn2+ homeostasis, NP cell proliferation and intervertebral disc rejuvenation. Collectively, our present study revealed a critical role of SYNJ2BP in maintaining mitochondrial Zn2+ homeostasis in NP cells during IDD progression, partially via sustaining MAM contact and NLRX1-SLC39A7 complex formation.

Mood instability and low back pain: a mendelian randomization study.

Objective: Low back pain is a prevalent and debilitating condition worldwide, with significant implications for individuals' quality of life and productivity. The aim of this study was to assess the relationship between mood instability and the risk of developing chronic low back pain, using a rigorously designed mendelian randomization methodology. Method: The study incorporated both univariate and multivariate mendelian randomization to analysis the causal relationship between mood instability and the risk of developing chronic low back pain. The data on mood instability from the Integrative Epidemiology Unit (IEU) opened Genome-Wide Association Studies (GWAS) project (IEU-opened GWAS project). Data on low back pain were collected from two sources: One source is the IEU open GWAS project (discovery data). Another source is a GWAS meta-analysis (replication data). Inverse variance weighted method, weighted median method, MR-Egger regression, and mendelian randomization pleiotropy residual sum and outlier method were used for mendelian randomization analysis. Result: The univariable mendelian randomization analysis shows a statistically significant correlation between mood instability and the risk of low back pain. Several methods were performed, including inverse variance weighting (discovery data: odds ratio = 3.544, 95% confidence interval = 1.785-7.039, p = 0.000; replication data: odds ratio = 3.167, 95% confidence interval = 2.476-4.052, p = 0.000), MR-Egger (discovery data: odds ratio = 7.178, 95% confidence interval = 0.057-909.525, p = 0.429; replication data: odds ratio = 2.262, 95% confidence interval = 0.580-8.825, p = 0.246), weighted median (discovery data: odds ratio = 2.730, 95% confidence interval = 1.112-6.702, p = 0.028; replication data: odds ratio = 3.243, 95% confidence interval = 2.378-4.422, p = 0.000), MR-PRESSO (discovery data: odds ratio = 3.544, 95% confidence interval = 1.785-7.039, p = 0.001; replication data: odds ratio = 3.167, 95% confidence interval = 2.476-4.052, p = 0.000) methods. The results were consistent across these methods. The results obtained from discovery data are consistent with those obtained from discovery data. In the multivariable mendelian randomization, after adjusting for various covariates such as body mass index, current tobacco smoking, alcohol intake frequency, Total body bone mineral density, and vigorous physical activity, there is a consistent correlation between mood instability and chronic low back pain. Conclusion: This study provides robust evidence supporting a causal relationship between mood instability and the development of low back pain. Our findings suggest that addressing mood instability may play a crucial role in prevention and management strategies for individuals experiencing low back pain.

Substance P enhances BMSC osteogenic differentiation via autophagic activation.

Bone mesenchymal stem cells (BMSCs) are the most commonly investigated progenitor cells in bone tissue engineering for treating severe bone defects. Strategies for regulating BMSC differentiation fate have received wide attention, in which redox homeostasis plays an important role due to the change in energy metabolism during stem cell differentiation. In the present study, it was observed that autophagic activity was induced along with BMSC osteogenic differentiation and subsequently regulated reactive oxygen species (ROS) generation and the level of osteogenesis. Furthermore, it was also observed that neuropeptide substance P (SP) administration could enhance the autophagic activity in rat BMSCs via the AMPK and mTOR pathways, as well as decreasing ROS generation and promoting osteogenic differentiation. Inhibition of autophagic activity by 3­MA reversed the effects of SP on ROS and osteogenic levels. The present results indicated that autophagic activity participated in the regulation of differentiation fate of BMSCs and SP could promote osteogenic differentiation by activating autophagy, providing a more precise biological mechanism for its application in bone tissue engineering.

Biomaterial-loaded allograft threaded cage for the treatment of femoral head osteonecrosis in a goat model.

The purpose of this study was to evaluate the efficacy of core decompression with a biomaterial-loaded allograft threaded cage (ATC) for the treatment of femoral head osteonecrosis in an established goat model. First, bilateral early-stage osteonecrosis was induced. After core decompression, the remaining goats were randomly divided into three groups: Group A, the goats were left without any treatment; Group B, the goats were treated with implanting a composite of autologous bone and decalcified bone matrix (DBM); Group C, the goats were treated using insertion of ATC loaded with DBM and autogenous bone graft. Then radiographic, histological and biomechanical analysis were taken in each group at 5, 10, and 20 weeks postoperation. In Group A, the classical signs of osteonecrosis of the femoral head were identified 10 weeks after the induction. Twenty weeks later, the density, surface and biomechanical stability of the femoral head were normal in Group C, while an irregular surface and an inhomogeneous microstructure or variation of density/hardness were identified in Group B. The specimens revealed a continuous trabaecular bone structure throughout the cage and extensive bone ingrowth and remodeling in Group C, while fibrous tissue was evident in Group B. Core decompression with a biomaterial loaded ATC almost uniformly delays or arrests the progression of the disease before articular collapse, and it could help to get the balance between bone resorption and new bone formation, strengthen structural mechanics of the femoral head, provide structure support of articular cartilage.