The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age. Surprisingly, Hippo pathway suppression was accompanied by overexpression of YAP, caused by acute disc injury, suggesting a limited ability for self-repair in IDD. We also demonstrated that YAP is inhibited by cell-to-cell contact via the Hippo pathway in vitro. Phosphorylation by large tumor suppressor kinases 1/2 (LATS1/2) led to cytoplasmic translocation and inactivation of YAP. YAP dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence. Moreover, NPCs were transfected with shYAP and it accelerates the premature senescence of cells by interfered Hippo pathway through YAP. Therefore, our results indicate that the Hippo pathway plays an important role in maintaining the homeostasis of intervertebral discs and controlling NPC proliferation.

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Notochord nucleus pulposus cells are characteristic of containing abundant and giant cytoplasmic vacuoles. This review explores the embryonic formation, biological function, and postnatal exhaustion of notochord vacuoles, aiming to characterize the signal network transforming the vacuolated nucleus pulposus cells into the vacuole-less chondrocytic cells. Embryonically, the cytoplasmic vacuoles within vertebrate notochord originate from an evolutionarily conserved vacuolation process during neurulation, which may continue to provide mechanical and signal support in constructing a mammalian intervertebral disc. For full vacuolation, a vacuolating specification from dorsal organizer cells, synchronized convergent extension, well-structured notochord sheath, and sufficient post-Golgi trafficking in notochord cells are required. Postnatally, age-related and species-specific exhaustion of vacuolated nucleus pulposus cells could be potentiated by Fas- and Fas ligand-induced apoptosis, intolerance to mechanical stress and nutrient deficiency, vacuole-mediated proliferation check, and gradual de-vacuolation within the avascular and compression-loaded intervertebral disc. These results suggest that the notochord vacuoles are active and versatile organelles for both embryonic notochord and postnatal nucleus pulposus, and may provide novel information on intervertebral disc degeneration to guide cell-based regeneration.

Study Design: Narrative review. Objectives: This review aims to present current applications of machine learning (ML) in spine domain to clinicians. Methods: We conducted a comprehensive PubMed search of peer-reviewed articles that were published between 2006 and 2020 using terms (spine, spinal, lumbar, cervical, thoracic, machine learning) to examine ML in spine. Then exclude research of other domain, case report, review or meta-analysis, and which without available abstract or full text. Results: Total 1738 articles were retrieved from database, and 292 studies were finally included. Key findings of current applications were compiled and summarized in this review. Main clinical applications of those techniques including image processing, diagnosis, decision supporting, operative assistance, rehabilitation, surgery outcomes, complications, hospitalization and cost. Conclusions: ML had achieved excellent performance and hold immense potential in spine. ML could help clinical staff to improve medical level, enhance work efficiency, and reduce adverse events. However more randomized controlled trials and improvement of interpretability are essential to clinicians accepting models’ assistance in real work.

Intervertebral disc (IVD) degeneration is closely related to inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α). The endoplasmic reticulum (ER) serves several important cell functions, which are essential for normal cell metabolism and survival. This study aims to clarify the role of ER stress and unfolded protein response (UPR) in TNF-α-induced biological changes in rat nucleus pulposus cells (NPCs) and IVD degeneration. In our research, rat NPCs were cultured with different concentrations of TNF-α in the presence or absence of ER stress inhibitors. Related genes and proteins were measured by immunofluorescence staining, quantitative real-time PCR, and Western blot analyses to monitor ER stress. Cell proliferation was evaluated by CCK-8 assay and cyclin D1 expression. Apoptosis was detected by flow cytometry and Western blot analyses. Our results showed that TNF-α induced the apoptosis of some NPCs in the early stage and then accelerated the proliferation of surviving cells. In addition, TNF-α stimulus upregulated ER stress markers and initiated UPR. However, these effects could be reversed by inhibitors, thereby reducing cell proliferation and enhancing apoptosis. In conclusion, ER stress reinforces the survival and proliferation of NPCs in TNF-α stimulus by activating UPR signaling, which could be an important therapeutic target in the future.