PIP5k1β is crucial to the generation of phosphotidylinosotol (4, 5)P₂. PIP5k1β participates in numerous cellular activities, such as B cell and platelet activation, cell phagocytosis and endocytosis, cell apoptosis, and cytoskeletal organization. In the present work, we aimed to examine the function of PIP5k1β in osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment. We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation. Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation. PIP5k1β^−/− osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity. PIP5k1β deficiency also promoted activation of mitogen-activated kinase and Akt signaling, enhanced TRAF6 and c-Fos expression, facilitated the expression and nuclear translocation of NFATC1, and upregulated Grb2 expression, thereby accelerating osteoclast differentiation and function. Finally, PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling. Therefore, PIP5k1β modulates bone homeostasis and remodeling.

Achieving effective drug delivery and therapeutic efficacy poses significant challenges in intervertebral disc degeneration (IDD). Here, we developed a dual-pathological cascade delivery system utilizing therapeutic mesenchymal stem cell-derived apoptotic vesicles (ApoVs). These vesicles are engineered with MMP13-responsive cell-penetrating peptides (MR-ApoVs) for targeted modulation of senescence. A reactive oxygen species (ROS)-responsive hydrogel incorporating CD44 aptamers (Apt-Gel) was developed to provide high-affinity retention and spatiotemporal controlled release of MR-ApoVs. In this system, MR-ApoV release is first triggered by hydrogel degradation in response to elevated ROS levels. Subsequently, the MMP13-responsive peptides on MR-ApoVs are activated to enhance their internalization into senescent nucleus pulposus (NP) cells, thereby achieving a sequential response to pathological signals within the degenerative disc microenvironment. In a rat model of IDD, MR-ApoV@Apt-Gel effectively attenuated NP cell senescence, restored extracellular matrix homeostasis, preserved disc hydration, and maintained intervertebral disc height. This dual-pathological cascade-responsive strategy represents a promising therapeutic approach for IDD treatment.

Study Design: Multicenter prospective observational study. Objective: To characterize the application and outcome profiles of TELD, IELD, and UBE in routine clinical practice. Summary of Background Data: Full-endoscopic lumbar surgery has been widely used in the treatment of lumbar disc herniation, yet multicenter prospective evidence on patient outcomes in real-world clinical practice remains limited. Methods: This multicenter prospective real-world study was conducted across 10 medical centers in four regions of China. Perioperative parameters, complications, and patient-reported outcome measures at postoperative day 1 and at 3, 6, and 12 months were recorded. Descriptive group comparisons were supplemented by adjusted repeated-measures analyses accounting for baseline outcome values, clinical covariates, operative level, and center. Results: A total of 623 patients were included: 105 in the TELD group, 109 in the IELD group, and 409 in the UBE group. Preoperative pain intensity, operative-level distribution, sensory deficit, and center distribution differed among groups. In adjusted analyses, TELD was associated with lower back-pain VAS than UBE at 3 months (mean difference, -0.73; 95% CI, -1.06 to -0.40; Holm P <0.001), 6 months (-0.51; -0.82 to -0.21; P =0.005), and 12 months (-0.77; -0.96 to -0.57; P <0.001). These differences were below the 3-point VAS MCID. Conclusions: TELD, IELD, and UBE were associated with favorable safety and midterm outcomes in this multicenter cohort. TELD was associated with modestly lower postoperative back-pain scores than UBE after adjustment for measured differences; however, the absolute differences did not reach the prespecified MCID and do not establish causal or universal procedural superiority. Level of Evidence: Level 3