Toward understanding the cellular control of vertebrate mineralization: The potential role of mitochondria.

This review examines the possible role of mitochondria in maintaining calcium and phosphate ion homeostasis and participating in the mineralization of bone, cartilage and other vertebrate hard tissues. The paper builds on the known structural features of mitochondria and the documented observations in these tissues that the organelles contain calcium phosphate granules. Such deposits in mitochondria putatively form to buffer excessively high cytosolic calcium ion concentrations and prevent metabolic deficits and even cell death. While mitochondria protect cytosolic enzyme systems through this buffering capacity, the accumulation of calcium ions by mitochondria promotes the activity of enzymes of the tricarboxylic acid (TCA/Krebs) cycle, increases oxidative phosphorylation and ATP synthesis, and leads to changes in intramitochondrial pH. These pH alterations influence ion solubility and possibly the transitions and composition in the mineral phase structure of the granules. Based on these considerations, mitochondria are proposed to support the mineralization process by providing a mobile store of calcium and phosphate ions, in smaller cluster or larger granule form, while maintaining critical cellular activities. The rise in the mitochondrial calcium level also increases the generation of citrate and other TCA cycle intermediates that contribute to cell function and the development of extracellular mineral. This paper suggests that another key role of the mitochondrion, along with the effects just noted, is to supply phosphate ions, derived from the breakdown of ATP, to endolysosomes and autophagic vesicles originating in the endoplasmic reticulum and Golgi and at the plasma membrane. These many separate but interdependent mitochondrial functions emphasize the critical importance of this organelle in the cellular control of vertebrate mineralization.

[Analysing hypertension in France : A call for an intersectional approach of the cascade of care]. / Analyse de l'hypertension en France : pour une analyse intersectionnelle de la cascade de soins.

In metropolitan France, estimates suggest that more than one in three adults has hypertension. Low-cost treatments are available, yet fewer than one in four hypertensive adults has a controlled level of hypertension below 140/90 mmHg. This rate is higher in other high-income countries such as Canada (65%) or Germany (52%).  Using a 'cascade of care' model, that decomposes the hypertension care continuum in awareness, treatment, and control, provides a better understanding of the origins of poor control. Furthermore, the theoretical framework of intersectionality, which simultaneously considers social positions of gender, class, and ethno-racial origin, could be used to understand the complexity of the social inequalities observed in hypertension-related outcomes. In this article we conducted a critical review of the international literature to identify new lines of analyses that could be applied to examine complex inequalities in France.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Microbubble cavitation restores Staphylococcus aureus antibiotic susceptibility in vitro and in a septic arthritis model.

Treatment failure in joint infections is associated with fibrinous, antibiotic-resistant, floating and tissue-associated Staphylococcus aureus aggregates formed in synovial fluid (SynF). We explore whether antibiotic activity could be increased against Staphylococcus aureus aggregates using ultrasound-triggered microbubble destruction (UTMD), in vitro and in a porcine model of septic arthritis. In vitro, when bacterially laden SynF is diluted, akin to the dilution achieved clinically with lavage and local injection of antibiotics, amikacin and ultrasound application result in increased bacterial metabolism, aggregate permeabilization, and a 4-5 log decrease in colony forming units, independent of microbubble destruction. Without SynF dilution, amikacin + UTMD does not increase antibiotic activity. Importantly, in the porcine model of septic arthritis, no bacteria are recovered from the SynF after treatment with amikacin and UTMD-ultrasound without UTMD is insufficient. Our data suggest that UTMD + antibiotics may serve as an important adjunct for the treatment of septic arthritis.

GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc.

Glycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose transporter, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and postnatal maintenance of the disc. Surprisingly, primary NP cells treated with 2 well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms. We showed in vitro that NP cells mitigated GLUT1 loss by rewiring glucose import through GLUT3. Of note, we demonstrated that substrates, such as glutamine and palmitate, did not compensate for glucose restriction resulting from dual inhibition of GLUT1/3, and inhibition compromised long-term cell viability. To investigate the redundancy of GLUT1 function in NP, we generated 2 NP-specific knockout mice: Krt19CreERT Glut1fl/fl and Foxa2Cre Glut1fl/fl. There were no apparent defects in postnatal disc health or development and maturation in mutant mice. Microarray analysis verified that GLUT1 loss did not cause transcriptomic alterations in the NP, supporting that cells are refractory to GLUT1 loss. These observations provide the first evidence to our knowledge of functional redundancy in GLUT transporters in the physiologically hypoxic intervertebral disc and underscore the importance of glucose as the indispensable substrate for NP cells.

Case report of interstitial keratitis in pregnancy.

Purpose: To report an unusual case of interstitial keratitis and lipid keratopathy in a pregnant woman with unknown etiology and atypical clinical course. Observations: A 15 weeks pregnant 32-year-old female daily soft contact lens wearer presented with 1 month of right eye redness and intermittent blurry vision. Slit lamp examination revealed sectoral interstitial keratitis with stromal neovascularization and opacification. No underlying ocular or systemic etiology was identified. The corneal changes were unresponsive to treatment with topical steroids and progressed over the ensuing months of her pregnancy. On continued follow up, the cornea demonstrated spontaneous partial regression of the opacification in the post-partum period. Conclusions and importance: This case illustrates a possible rare manifestation of pregnancy physiology in the cornea. It also emphasizes the utility of close follow-up and conservative management in pregnant patients with idiopathic interstitial keratitis not only to avoid intervention during pregnancy but also because of the possibility of spontaneous improvement or resolution of the corneal changes.

Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc.

Hypoxia-inducible factors (HIFs) are critical to the development and homeostasis of hypoxic tissues. Although HIF-2α, one of the main HIF-α isoforms, is expressed in nucleus pulposus (NP) cells, its functions remain unknown. We deleted HIF-2α in the NP tissue using a notochord-specific FoxA2Cre allele to study HIF-2α function in the adult intervertebral disc. Unlike observations in HIF-1αcKO mice, fate mapping studies using Rosa26-mTmG reporter showed that HIF-2α loss in NP did not negatively impact cell survival or affect compartment development. Rather, loss of HIF-2α resulted in slightly better attributes of NP morphology in 14-month-old HIF-2αcKO mice as evident from lower scores of degeneration. These 14-month-old HIF-2αcKO mice also exhibited significant reduction in NP tissue fibrosis and lower collagen turnover in the annulus fibrosis (AF) compartment. Imaging-Fourier transform-infrared (FTIR) analyses showed decreased collagen and protein content in the NP and maintained chondroitin sulfate levels in 14-month-old HIF-2αcKO . Mechanistically, global transcriptomic analysis showed enrichment of differentially expressed genes with Gene Ontology (GO) terms related to metabolic processes and cell development, molecular functions concerned with histone and protein binding, and associated pathways, including oxidative stress. Noteworthy, these morphological differences were not apparent in 24-month-old HIF-2αcKO , indicating that aging is the dominant factor in governing disc health. Together these data suggest that loss of HIF-2α in the NP compartment is not detrimental to the intervertebral disc development but rather mitigates NP tissue fibrosis and offers mild but transient protection from age-dependent early degenerative changes. © 2022 American Society for Bone and Mineral Research (ASBMR).

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

The psychological effects of COVID-19-related containment in children: The E-COCCON French study.

The first containment of the Sars-Cov2 pandemic had the potential to generate posttraumatic stress (PTS) symptoms in children. OBJECTIVE: The main objective of the study was to determine the prevalence of PTS symptoms within 6 weeks of the end of lockdown, in children contained between March 17, 2020 and May 11, 2020 in France. MATERIAL AND METHODS: This was a French prospective cross-sectional study between May 15 and July 2, 2020 conducted via telephone survey. Parents of children aged between 8 and 15 years were eligible. The invitation to participate was proposed through social networks (Instagram and Facebook), various local and national media, and by e-mail to the staff of our University Hospital Center. The PTS symptoms were assessed using the CRIES-13. A score of 30 and over has been confirmed as the cut-off for screening cases. RESULTS: During the study period, 379 children (male, n = 207) were included, their mean age was 10.8±2.1 years. Symptoms of PTSD were identified in 17% of the children (girls 20.5%, boys 13.5%). These children were younger (p = 0.04), lacked access to a private outdoor space (p < 0.0001; OR: 7.8), had parents whose profession exposed them more to the coronavirus, and had parents who were more afraid of COVID-19. CONCLUSION: After the first lockdown related to the pandemic crisis, children developed PTSD symptoms. The onset of such symptoms is correlated with gender, age, lockdown conditions, and parental perceptions. These last considerations were worse for pink- or blue-collar families, attesting to the subsequent intensification of health inequalities.

Abcc6 Null Mice-a Model for Mineralization Disorder PXE Shows Vertebral Osteopenia Without Enhanced Intervertebral Disc Calcification With Aging.

Chronic low back pain is a highly prevalent health condition intricately linked to intervertebral disc degeneration. One of the prominent features of disc degeneration that is commonly observed with aging is dystrophic calcification. ATP-binding cassette sub-family C member 6 (ABCC6), a presumed ATP efflux transporter, is a key regulator of systemic levels of the mineralization inhibitor pyrophosphate (PPi). Mutations in ABCC6 result in pseudoxanthoma elasticum (PXE), a progressive human metabolic disorder characterized by mineralization of the skin and elastic tissues. The implications of ABCC6 loss-of-function on pathological mineralization of structures in the spine, however, are unknown. Using the Abcc6 -/- mouse model of PXE, we investigated age-dependent changes in the vertebral bone and intervertebral disc. Abcc6 -/- mice exhibited diminished trabecular bone quality parameters at 7 months, which remained significantly lower than the wild-type mice at 18 months of age. Abcc6 -/- vertebrae showed increased TRAP staining along with decreased TNAP staining, suggesting an enhanced bone resorption as well as decreased bone formation. Surprisingly, however, loss of ABCC6 resulted only in a mild, aging disc phenotype without evidence of dystrophic mineralization. Finally, we tested the utility of oral K3Citrate to treat the vertebral phenotype since it is shown to regulate hydroxyapatite mechanical behavior. The treatment resulted in inhibition of the osteoclastic response and an early improvement in mechanical properties of the bone underscoring the promise of potassium citrate as a therapeutic agent. Our data suggest that although ectopic mineralization is tightly regulated in the disc, loss of ABCC6 compromises vertebral bone quality and dysregulates osteoblast-osteoclast coupling.

Peripheral Hypertrophic Subepithelial Corneal Degeneration.

PURPOSE: The purpose of this study was to report a large series of patients with peripheral hypertrophic subepithelial corneal degeneration (PHSCD) and differentiate the condition from Salzmann nodular degeneration (SND). METHODS: We retrospectively reviewed the charts of 49 patients diagnosed with PHSCD and reported their clinical, refractive, and topographic/tomographic findings. RESULTS: Most of the eyes were white and quiet. Minimal variable injection was present in a few eyes usually in the presence of pseudopterygium. Typical corneal involvement consists of peripheral circumferential-elevated whitish subepithelial opacities with fine superficial vessels along the limbus and linear deposits of iron in the epithelium along the central edge of the opacification. The typical topographic/tomographic findings consist of flattening directly over the corneal opacification with central flattening aligning with the axis of the opacification. In all subjects, the mean refractive astigmatism was significantly less than the mean topographic/tomographic Sim K astigmatism. Thirty-five eyes underwent surgical excision. The surgical eyes demonstrated significantly less astigmatism and better best-spectacle corrected visual acuity than pre-op. Moreover, all the eyes that underwent surgery for discomfort experienced significant improvement in their symptoms. Histopathology of the keratectomy specimens demonstrated paucicellular subepithelial fibrosis with overlying epithelium that was variable in caliber. CONCLUSIONS: PHSCD is distinct from SND, primarily occurring in middle-aged women, bilateral and fairly symmetric with larger more peripheral opacities than SND, and absence of inflammatory signs and symptoms.

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function.

Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress.

Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice.

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration.

The role of HIF proteins in maintaining the metabolic health of the intervertebral disc.

The physiologically hypoxic intervertebral disc and cartilage rely on the hypoxia-inducible factor (HIF) family of transcription factors to mediate cellular responses to changes in oxygen tension. During homeostatic development, oxygen-dependent prolyl hydroxylases, circadian clock proteins and metabolic intermediates control the activities of HIF1 and HIF2 in these tissues. Mechanistically, HIF1 is the master regulator of glycolytic metabolism and cytosolic lactate levels. In addition, HIF1 regulates mitochondrial metabolism by promoting flux through the tricarboxylic acid cycle, inhibiting downsteam oxidative phosphorylation and controlling mitochondrial health through modulation of the mitophagic pathway. Accumulation of metabolic intermediates from HIF-dependent processes contribute to intracellular pH regulation in the disc and cartilage. Namely, to prevent changes in intracellular pH that could lead to cell death, HIF1 orchestrates a bicarbonate buffering system in the disc, controlled by carbonic anhydrase 9 (CA9) and CA12, sodium bicarbonate cotransporters and an intracellular H+/lactate efflux mechanism. In contrast to HIF1, the role of HIF2 remains elusive; in disorders of the disc and cartilage, its function has been linked to both anabolic and catabolic pathways. The current knowledge of hypoxic cell metabolism and regulation of HIF1 activity provides a strong basis for the development of future therapies designed to repair the degenerative disc.

Benchmarking Adenoma Detection Rates for Colonoscopy: Results From a US-Based Registry.

INTRODUCTION: Adenoma detection rate (ADR) is highly variable across practices, and national or population-based estimates are not available. Our aim was to study the ADR, variability of rates over time, and factors associated with detection rates of ADR in a national sample of patients undergoing colonoscopy. METHODS: We used colonoscopies submitted to the GI Quality Improvement Consortium, Ltd. registry from 2014 to 2018 on adults aged 50-89 years. We used hierarchical logistic models to study factors associated with ADR. RESULTS: A total of 2,646,833 colonoscopies were performed by 1,169 endoscopists during the study period. The average ADR for screening colonoscopies per endoscopist was 36.80% (SD 10.21), 44.08 (SD 10.98) in men and 31.20 (SD 9.65) in women. Adjusted to the US population, the ADR was 39.08%. There was a significant increase in ADR from screening colonoscopies over the study period from 33.93% in 2014 to 38.12% in 2018. DISCUSSION: The average ADR from a large national US sample standardized to the US population is 39.05% and has increased over time.

Hypoxia and Hypoxia-Inducible Factor-1α Regulate Endoplasmic Reticulum Stress in Nucleus Pulposus Cells: Implications of Endoplasmic Reticulum Stress for Extracellular Matrix Secretion.

Endoplasmic reticulum (ER) stress is shown to promote nucleus pulposus (NP) cell apoptosis and intervertebral disc degeneration. However, little is known about ER stress regulation by the hypoxic disc microenvironment and its contribution to extracellular matrix homeostasis. NP cells were cultured under hypoxia (1% partial pressure of oxygen) to assess ER stress status, and gain-of-function and loss-of-function approaches were used to assess the role of hypoxia-inducible factor (HIF)-1α in this pathway. In addition, the contribution of ER stress induction on the NP cell secretome was assessed by a nontargeted quantitative proteomic analysis by sequential windowed data independent acquisition of the total high-resolution mass spectra-mass spectrometry. NP cells exhibited a lower ER stress burden under hypoxia. Knockdown of HIF-1α increased C/EBP homologous protein, protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) levels, whereas HIF-1α stabilization decreased the expression of ER stress markers Ddit3, Hsp5a, Atf6, and Eif2a. Interestingly, ER stress inducers tunicamycin and thapsigargin induced HIF-1α activity under hypoxia while promoting the unfolded protein response. NP cell secretome analysis demonstrated an impact of ER stress induction on extracellular matrix secretion, with decreases in collagens and cell adhesion-related proteins. Moreover, analysis of transcriptomic data of NP tissues from aged mice and degenerated human discs showed higher levels of unfolded protein response markers and decreased levels of matrix components. Our study shows, for the first time, that hypoxia and HIF-1α attenuate ER stress responses in NP cells, and ER stress promotes inefficient extracellular matrix secretion under hypoxia.

Human pluripotent stem cell-derived lung organoids: Potential applications in development and disease modeling.

The pulmonary system is comprised of two main compartments, airways and alveolar space. Their tissue and cellular complexity ensure lung function and protection from external agents, for example, virus. Two-dimensional (2D) in vitro systems and animal models have been largely employed to elucidate the molecular mechanisms underlying human lung development, physiology, and pathogenesis. However, neither of these models accurately recapitulate the human lung environment and cellular crosstalk. More recently, human-derived three-dimensional (3D) models have been generated allowing for a deeper understanding of cell-to-cell communication. However, the availability and accessibility of primary human cell sources from which generate the 2D and 3D models may be limited. In the past few years, protocols have been developed to successfully employ human pluripotent stem cells (hPSCs) and differentiate them toward pulmonary fate in vitro. In the present review, we discuss the advantages and pitfalls of hPSC-derived lung 2D and 3D models, including the main characteristics and potentials for these models and their current and future applications for modeling development and diseases. Lung organoids currently represent the closest model to the human pulmonary system. We further focus on the applications of lung organoids for the study of human diseases such as pulmonary fibrosis, infectious diseases, and lung cancer. Finally, we discuss the present limitations and potential future applications of 3D lung organoids. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion.

Sox9 deletion causes severe intervertebral disc degeneration characterized by apoptosis, matrix remodeling, and compartment-specific transcriptomic changes.

SOX9 plays an important role in chondrocyte differentiation and, in the developing axial skeleton, maintains the notochord and the demarcation of intervertebral disc compartments. Diminished expression is linked to campomelic dysplasia, resulting in severe scoliosis and progressive disc degeneration. However, the specific functions of SOX9 in the adult spinal column and disc are largely unknown. Accordingly, employing a strategy to conditionally delete Sox9 in Acan-expressing cells (AcanCreERT2Sox9fl/fl), we delineated these functions in the adult intervertebral disc. AcanCreERT2Sox9fl/fl mice (Sox9cKO) showed extensive and progressive remodeling of the extracellular matrix in nucleus pulposus (NP) and annulus fibrosus (AF), consistent with human disc degeneration. Progressive degeneration of the cartilaginous endplates (EP) was also evident in Sox9cKO mice, and it preceded morphological changes seen in the NP and AF compartments. Fate mapping using tdTomato reporter, EdU chase, and quantitative immunohistological studies demonstrated that SOX9 is crucial for disc cell survival and phenotype maintenance. Microarray analysis showed that Sox9 regulated distinct compartment-specific transcriptomic landscapes, with prominent contributions to the ECM, cytoskeleton-related, and metabolic pathways in the NP and ion transport, the cell cycle, and signaling pathways in the AF. In summary, our work provides new insights into disc degeneration in Sox9cKO mice at the cellular, molecular, and transcriptional levels, underscoring tissue-specific roles of this transcription factor. Our findings may direct future cell therapies targeting SOX9 to mitigate disc degeneration.