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Intervertebral disc degeneration is a natural process during aging and a leading cause of lower back pain. Here, we generate a comprehensive atlas of nucleus pulposus cells using single-cell RNA-seq analysis of human nucleus pulposus tissues (three males and four females, age 41.14 ± 18.01 years). We identify fibrotic late-stage nucleus pulposus cells characterized by upregulation of serglycin expression which facilitate the local inflammatory response by promoting the infiltration of inflammatory cytokines and macrophages. Finally, we discover that daphnetin, a potential serglycin ligand, substantially mitigates the local inflammatory response by downregulating serglycin expression in an in vivo mouse model, thus alleviating intervertebral disc degeneration. Taken together, we identify late-stage nucleus pulposus cells and confirm the potential mechanism by which serglycin regulates intervertebral disc degeneration. Our findings indicate that serglycin is a latent biomarker of intervertebral disc degeneration and may contribute to development of diagnostic and therapeutic strategies. Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.

Intervertebral disc degeneration (IVDD) is a main cause of low back pain, and inflammatory factors play key roles in its pathogenesis. Gremlin-1 (Grem1) was reported to induce an inflammatory response in other fields. This study aimed to investigate the mechanisms of Grem1 in the degenerative process of intervertebral discs. Dysregulated genes were determined by analyzing microarray profiles. The expression of Grem1 in 17 human disc samples (male:female = 9:8) and rat models ( n  = 5 each group) was measured by western blotting (WB), real-time quantitative PCR (RT-qPCR), and immunohistochemistry (IHC). The regulatory effects of Grem1 on apoptosis were examined using siRNAs, flow cytometry, immunofluorescence (IF), and WB. The therapeutic effect was evaluated by locally injecting specific Grem1 siRNA into IVDD rats. The expression of Grem1 was significantly increased in human degenerative intervertebral discs; furthermore, the expression of Grem1 positively correlated with the level of intervertebral disc degeneration. Grem1 was significantly overexpressed in tumor necrosis factor (TNF)-α-induced degenerative NP cells. Apoptosis in degenerative NP cells transfected with siRNA targeting Grem1 was significantly lower than that in the control group. Specific Grem1 siRNA markedly repressed the development of IVDD in surgery-induced IVDD rats. These results indicated that the expression of Grem1 was positively correlated with the severity of intervertebral disc degeneration, and Grem1 siRNA could inhibit Grem1-induced apoptosis and extracellular matrix alterations by mediating the TGF-β/Smad signaling pathway. This study may provide a therapeutic strategy for alleviating inflammation-induced apoptosis associated with intervertebral disc degeneration. Disc generation: Protein identified as potential therapeutic target Gene expression profiling reveals an important factor underlying degeneration of the discs that connect and cushion individual vertebrae, a primary cause of lower back pain. This degeneration generally originates in the central portion of the disc known as the nucleus pulposus (NP). Researchers led by Jianru Wang and Zhaomin Zheng of the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, compared NP cells from healthy individuals with those from patients with disc degeneration. They observed strongly increased expression of a protein called Gremlin-1, which is critical to development and also associated with osteoarthritis. Gremlin-1 expression correlated strongly with degeneration and death in cultured NP cells, and the researchers identified key signaling pathways affected by this protein. Targeted inhibition of Gremlin-1 prevented tissue damage in a rat model of disc degeneration, highlighting a potential therapeutic opportunity.

Oxytocin (OT) is a neuropeptide known to affect social behavior and cognition. The epigenetic modification of the oxytocin receptor (OTR) via DNA methylation stimulates parturition and breast milk secretion and inhibits craniopharyngioma, breast cancer, and ovarian cancer growth significantly as well as directly regulates bone metabolism in their peripheral form rather than the central form. OT and OTR can be expressed on bone marrow mesenchymal stem cells (BMSCs), osteoblasts (OB), osteoclasts (OC), osteocytes, chondrocytes, and adipocytes. OB can synthesize OT under the stimulation of estrogen as a paracrine–autocrine regulator for bone formation. OT/OTR, estrogen, and OB form a feed-forward loop through estrogen mediation. The osteoclastogenesis inhibitory factor (OPG)/receptor activator of the nuclear factor kappa-B ligand (RANKL) signaling pathway is crucially required for OT and OTR to exert anti-osteoporosis effect. Downregulating the expression of bone resorption markers and upregulating the expression of the bone morphogenetic protein, OT could increase BMSC activity and promote OB differentiation instead of adipocytes. It could also stimulate the mineralization of OB by motivating OTR translocation into the OB nucleus. Moreover, by inducing intracytoplasmic Ca 2+ release and nitric oxide synthesis, OT could regulate the OPG/RANKL ratio in OB and exert a bidirectional regulatory effect on OC. Furthermore, OT could increase the activity of osteocytes and chondrocytes, which helps increase bone mass and improve bone microstructure. This paper reviews recent studies on the role of OT and OTR in regulating cells in bone metabolism as a reference for their clinical use and research based on their reliable anti-osteoporosis effects.

Heart failure (HF) is a terminal cardiovascular syndrome related to systemic hypoxia. Hypoxia is considered a fundamental pathophysiological process, and the resulting tissue response depends on the severity and duration of exposure. Hypoxia-inducible factors (HIFs) promote adaptation to hypoxic conditions by regulating the expression of multiple hypoxia-responsive genes. Its short-term activation during acute hypoxia exerts cardioprotective effects, whereas chronic activation induces pathological hypertrophy, depending on the disease context. Therefore, HIF-mediated hypoxic responses in HF may involve hierarchical adaptations to hypoxia. This review discusses the role of HIFs in the physiology and pathology of HF, focusing on metabolic remodeling, angiogenesis, cardiac inflammation, and circadian influences, as well as their potential effects on myocardial performance. Furthermore, the therapeutic potential of HIF-targeting compounds in HF treatment will be reviewed. Overall, whether targeting HIF-induced changes in HF is an effective strategy remains to be established; thus, research in this field is urgently needed.

Circular RNAs (circRNAs) play important roles in the initiation and development of different diseases. Here, we detected their role in intervertebral disc (IVD) degeneration. An Arraystar human circular RNA microarray assay was used to detect circRNAs in normal and degenerated human IVD nucleus pulposus (NP) tissues. The role of circ-4099 in IVDD and its mechanism were evaluated by qRT-PCR and gain-of-function/loss-of-function studies. Interaction networks for competing endogenous RNAs (ceRNAs), miRNAs, and miRNA target gene were detected by bioinformatics analysis, RNA immunoprecipitation and luciferase assay. Expression of seventy-two circRNAs were increased by more than twofold in degenerated NP tissues. qRT-PCR showed that the expression of circ-4099 in NP tissues was consistent with that of the array screening. Over-expression of circ-4099 increased the expression of Collagen II and Aggrecan and decreased the secretion of the pro-inflammatory factors IL-1β, TNF-α, and PGE2. TNF-α treatment increased circ-4099 expression in NP cells. NF-κB/MAPK inhibitors or shRNAs abolished the inductive effects of TNF-α on circ-4099 expression. We further demonstrated that circ-4099 was able to function as a “sponge” by competitively binding miR-616-5p, which reversed the suppression of Sox9 by miR-616-5p. We used DNA pull-down and spectrometry experiments to show that TNF-α can promote circ-4099 transcription through upregulation of GRP78. We provide the first evidence that shows circRNAs are differentially expressed in degenerated and normal NP tissues. Circ-4099 may play a role in a protective mechanism and be part of a compensatory response that maintains the synthesis and secretion of the extracellular matrix in NP cells and might be a protective factor in IVD degeneration as well as restore NP cell function. Spinal disease: Circular RNA linked to disc degeneration A circular RNA molecule helps protect against degenerative disc disease. Hua Wang and coworkers from Sun Yat-Sen University in Guangzhou, China, examined whether circular RNAs, regulatory molecules that take the form of closed RNA loops, contribute to intervertebral disc degeneration, a condition in which connective tissue in the spine breaks down over time, causing back pain and weakness. They found 72 circular RNAs that were either significantly over- or under-expressed in the inner core tissue of intervertebral discs from patients with this condition. They showed that one of these circular RNAs, circ-4099, increased the production of key cartilage proteins. This RNA also blocked the activity of another non-circular regulatory RNA that normally inhibits a molecular pathway needed for proper cartilage formation. Enhancing the activity of this protective molecule could help treat degenerative disc disease.

Inadequate tendon healing and heterotopic bone formation result in substantial pain and disability, yet the specific cells responsible for tendon healing remain uncertain. Here we identify a CD26 + tendon stem/progenitor cells residing in peritendon, which constitutes a primitive stem cell population with self-renewal and multipotent differentiation potentials. CD26 + tendon stem/progenitor cells migrate into the tendon midsubstance and differentiation into tenocytes during tendon healing, while ablation of these cells led to insufficient tendon healing. Additionally, CD26 + tendon stem/progenitor cells contribute to heterotopic ossification and Tenascin-C-Hippo signaling is involved in this process. Targeting Tenascin-C significantly suppresses chondrogenesis of CD26 + tendon stem/progenitor cells and subsequent heterotopic ossification. Our findings provide insights into the identification of tendon stem/progenitor cells and illustrate the essential role of CD26 + tendon stem/progenitor cells in tendon healing and heterotopic bone formation. Chen, et al identify peritendon CD26 expressing tendon stem/progenitor cells that contribute to tendon healing, as well as Tenascin-C/YAP dependent heterotopic ossification.

Background Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis. Methods Recombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed. Results Recombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Conclusions The current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.

Purpose To investigate the association between intravenous methylprednisolone administration and the risk of surgical site infection (SSI) following posterior lumbar fusion (PLF) surgery. Methods This retrospective, single-center study analyzed data from 800 adult patients who underwent elective PLF surgery at our institution. Patients were classified according to postoperative intravenous methylprednisolone administration. Univariate and multivariable logistic regression, and subgroup analysis were used to assess the association between methylprednisolone administration and SSI risk, as well as its impact on postoperative pain management. Results Our analysis showed no significant association between intravenous methylprednisolone administration and the development of a SSI after PLF. Subgroup analyses suggested that methylprednisolone was potentially protective in patients with a body mass index (BMI) < 25 kg/m 2 . In addition, patients treated with methylprednisolone had significantly lower pain scores in the early postoperative period, and lower incidence of postoperative nausea and vomiting (PONV) compared to patients not treated with methylprednisolone. However, there was no significant difference in pain scores between the 2 groups at 4 weeks postoperatively. Conclusions This study suggests that intravenous methylprednisolone administration may not increase the risk of SSI after single-level PLF. In addition, it appears to have a beneficial effect on postoperative pain management and PONV, especially during the early recovery phase.

Oxidative stress and aging lead to progressive senescence of nucleus pulposus (NP) cells, resulting in intervertebral disc (IVD) degeneration (IVDD). In some cases, degenerative IVD can further cause low back pain (LBP). Several studies have confirmed that delaying and rejuvenating the senescence of NP cells can attenuate IVDD. However, the relatively closed tissue structure of IVDs presents challenges for the local application of anti-senescence drugs. Here, we prepared an anti-senescence hydrogel by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with quercetin to alleviate IVDD by removing senescent NP cells. The hydrogel exhibited injectability, biodegradability, prominent biocompatibility and responsive release of quercetin under pathological conditions. In vitro experiments demonstrated that the hydrogel could reduce the expression of senescence markers and restore the metabolic balance in senescent NP cells. In vivo studies validated that a single injection of the hydrogel in situ could maintain IVD tissue structure and alleviate sensitivity to noxious mechanical force in the rat models, indicating a potential therapeutic approach for ameliorating IVDD and LBP. This approach helps prevent potential systemic toxicity associated with systemic administration and reduces the morbidity resulting from repeated injections of free drugs into the IVD, providing a new strategy for IVDD treatment. [Display omitted] •Quercetin can be released in a pH responsive manner from the GPQ hydrogel.•The GPQ hydrogel attenuates oxidative stress and replicative senescence of NP cells.•A concentration of 50 μM GPQ hydrogel delays IVDD in aged rats.•PAT result shows that the GPQ hydrogel alleviates sensitivity of degenerative IVD to mechanical pain.

Tissue optical clearing enables imaging deeper in large volumes with high-resolution. Clear T2 is a relatively rapid clearing method with no use of solvents or detergents, hence poses great advantage on preservation of diverse fluorescent labels. However, this method suffers from insufficient tissue transparency, especially for adult mouse brain blocks. In this work, we develop a rapid and versatile clearing method based on Clear T2 , termed RTF (Rapid clearing method based on Triethanolamine and Formamide), aiming for better clearing capability. The results show that RTF can not only efficiently clear embryos, neonatal brains and adult brain blocks, but also preserve fluorescent signal of both endogenous fluorescent proteins and lipophilic dyes, and be compatible with virus labeling and immunostaining. With the good transparency and versatile compatibility, RTF allows visualization and tracing of fluorescent labeling cells and neuronal axons combined with different imaging techniques, showing potentials in facilitating observation of morphological architecture and visualization of neuronal networks.