BACKGROUND
Intervertebral disc (IVD) degeneration (IDD) is a leading cause of low back pain, with limited treatment options. The degenerative disc's harsh microenvironment promotes nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) death and hinders self repair. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an atypical neurotrophic factor, has protective effects in degenerative diseases. However, its role in IDD is unclear.
METHODS
Assessment of MANF expression was conducted in both human nucleus pulposus tissues and a rat IVD puncture model. An in vitro model of degeneration was established by acid treatment of NP-MSCs, and the functional role of MANF was explored through its knockdown and overexpression. RNA sequencing was employed to identify downstream targets. The therapeutic potential of MANF-overexpressing NP-MSCs was evaluated in a rat puncture model.
RESULTS
MANF expression was markedly downregulated in degenerated IVD tissues from both human patients and rat models. Correspondingly, in vitro experiments demonstrated that MANF knockdown exacerbated, while its overexpression mitigated, acid-induced apoptosis of NP-MSCs. Mechanistically, MANF attenuated mitochondrial dysfunction and ER stress of NP-MSCs under acidic conditions by maintaining MAM integrity, as demonstrated by the complete abolition of this protection upon treatment with the MAM uncoupler FATE1. Transcriptomic analysis and subsequent validation identified receptor expression-enhancing protein 1 (REEP1) as a critical downstream effector through which MANF safeguards MAM integrity. We further elucidated that MANF upregulates REEP1 expression by directly inhibiting miR-33b-5p. In vivo, transplantation of MANF-overexpressing NP-MSCs effectively attenuated IDD in a rat model.
CONCLUSION
MANF protected NP-MSCs from acidosis by sustaining MAM integrity via the MiR-33b-5p/REEP1 axis. These findings reveal MANF's mechanism and therapeutic potential for IDD.
Chen-Hao Zhao, Liang Kang, Jiaqi Wang et al.· Cell Biology and Toxicology· 0 citations
OBJECTIVE
This study compared Hounsfield unit (HU) measurements obtained from different regions of interest (ROIs) on lumbar CT for assessing bone mineral density (BMD) and discriminating osteoporosis and thoracolumbar fragility fracture status, aiming to evaluate whether ROI selection meaningfully influences HU-based assessment.
METHODS
Five HU measurement methods were evaluated using lumbar CT. Their correlations with dual-energy X-ray absorptiometry (DEXA)-derived BMD and their discriminative performance for osteoporosis and thoracolumbar fragility fracture status were analyzed. Receiver operating characteristic (ROC) curves were constructed, and pairwise comparisons of areas under the curve (AUCs) were performed using the DeLong test. A sensitivity analysis was additionally conducted after excluding substituted vertebral levels and recalculating mean lumbar HU using only non-substituted vertebrae.
RESULTS
All five HU measurement methods showed significant correlations with DEXA-derived BMD, and no statistically significant differences in discriminative performance were observed among the five ROI methods in the primary analysis. In the sensitivity analysis excluding substituted vertebral levels, the AUCs remained comparable across methods for osteoporosis (0.816-0.826) and thoracolumbar fragility fracture status (0.677-0.689), with all pairwise DeLong tests showing no statistically significant differences (all p > 0.05).
CONCLUSION
Different lumbar CT ROI methods demonstrated comparable performance in assessing BMD and discriminating thoracolumbar fragility fracture status, and sensitivity analysis confirmed that exclusion of substituted vertebral levels did not materially affect the results. No ROI method showed statistically significant superiority, suggesting that ROI selection may be guided by clinical feasibility and workflow convenience rather than by diagnostic performance alone.
ADVANCES IN KNOWLEDGE
This study compares five commonly used lumbar CT HU measurement methods and shows that their performance is broadly similar. The findings suggest that ROI selection may be guided primarily by clinical feasibility and workflow convenience, although further external validation is required before routine clinical application.
