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Communication between osteoblasts and endothelial cells (ECs) is essential for bone turnover, but the molecular mechanisms of such communication are not well defined. Here we identify Cxcl9 as an angiostatic factor secreted by osteoblasts in the bone marrow microenvironment. We show that Cxcl9 produced by osteoblasts interacts with vascular endothelial growth factor and prevents its binding to ECs and osteoblasts, thus abrogating angiogenesis and osteogenesis both in mouse bone and in vitro . The mechanistic target of rapamycin complex 1 activates Cxcl9 expression by transcriptional upregulation of STAT1 and increases binding of STAT1 to the Cxcl9 promoter in osteoblasts. These findings reveal the essential role of osteoblast-produced Cxcl9 in angiogenesis and osteogenesis in bone, and Cxcl9 can be targeted to elevate bone angiogenesis and prevent bone loss-related diseases. Bone development and vascularization are coupled events that share many molecular mechanisms. Here the authors identify osteoblast-secreted Cxcl9 as an inhibitory regulator of angiogenesis and osteogenesis, and show that mTORC1 signaling and STAT1 are critical upstream mediators of the cytokine expression.

Osteoporosis (OP) is the most common systematic bone disorder among elderly individuals worldwide. Long noncoding RNAs (lncRNAs) are involved in biological processes in various human diseases. It has been previously revealed that PAX8 antisense RNA 1 (PAX8-AS1) is upregulated in OP. However, its molecular mechanism in OP remains unclear. Therefore, we specifically designed this study to determine the specific role of PAX8-AS1 in OP. We first established a rat model of OP and then detected PAX8-AS1 expression in the rats with RT-qPCR. Next, to explore the biological function of PAX8-AS1 in osteoblasts, in vitro experiments, such as Cell Counting Kit-8 (CCK-8) assays, flow cytometry, western blotting and immunofluorescence (IF) staining, were conducted. Subsequently, we performed bioinformatic analysis and luciferase reporter assays to predict and identify the relationships between microRNA 1252-5p (miR-1252-5p) and both PAX8-AS1 and G protein subunit beta 1 (GNB1). Additionally, rescue assays in osteoblasts clarified the regulatory network of the PAX8-AS1/miR-1252-5p/GNB1 axis. Finally, in vivo loss-of-function studies verified the role of PAX8-AS1 in OP progression. The results illustrated that PAX8-AS1 was upregulated in the proximal tibia of OP rats. PAX8-AS1 silencing promoted the viability and inhibited the apoptosis and autophagy of osteoblasts. PAX8-AS1 interacted with miR-1252-5p. GNB1 was negatively regulated by miR-1252-5p. In addition, the impacts of PAX8-AS1 knockdown on osteoblasts were counteracted by GNB1 overexpression. PAX8-AS1 depletion suppressed OP progression by inhibiting apoptosis and autophagy in osteoblasts. In summary, PAX8-AS1 suppressed the viability and activated the autophagy of osteoblasts via the miR-1252-5p/GNB1 axis in OP. Osteoporosis: An RNA molecule that suppresses bone-building A recently identified regulatory RNA molecule contributes to osteoporosis by suppressing production of a protein that promotes survival of bone-building osteoblast cells. These regulatory RNA molecules do not encode proteins, but instead regulate gene expression by binding and inactivating complementary RNA strands. Researchers led by Yiyan Qiu at Southern Medical University in Guangzhou, China, have now learned how one such RNA facilitates bone degeneration in osteoporosis. Qiu and colleagues show that this RNA interferes with the production of a protein that is essential to the metabolic health and survival of osteoblasts, promoting bone loss in a rat model of osteoporosis. Experimental techniques that selectively deplete this RNA help preserve the viability of the osteoblast population. This depletion could provide a useful approach for future drug development efforts.

Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that methyltransferase-like 3 (METTL3), the first methyltransferase to be identified, acted as an oncogene or tumor suppressor in multiple human cancers. However, its functions and underlying mechanisms in OS progression remain unclear; therefore, we explored these processes. Methods: We used real-time quantitative PCR (RT-qPCR) and Western blot assays to explore METTL3 expression in OS tumor tissues and five OS cell lines to assess its clinical significance. To further examine the functional role of METTL3 during OS progression, CCK-8 analyses, transwell assays, and xenograft model studies were conducted after silencing METTL3. Additionally, underlying mechanisms were also explored using RIP-seq and RIP-qPCR approaches. Results: METTL3 was upregulated in OS tumor tissues and cell lines and was associated with a worse prognosis. Moreover, METTL3 silencing suppressed OS cell proliferation, migration, and invasion. Also, in vivo METTL3 oncogenic functions were confirmed in the x enograft model. Comprehensive mechanistic analyses identified long non-coding RNA (lncRNA) DANCR as a potential target of METTL3, as indicated by reduced DANCR levels after METTL3 silencing. Also, lncRNA DANCR knockdown repressed OS cell proliferation, migration, and invasion. Furthermore, both METTL3 and lncRNA DANCR silencing significantly suppressed OS growth and metastasis. Finally, we hypothesized that METTL3 regulated DANCR expression via m6A modification-mediated DANCR mRNA stability. Conclusion: METTL3 contributes to OS progression by increasing DANCR mRNA stability via m6A modification, meaning that METTL3 may be a promising therapeutic target for OS treatment.

Recently, accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis (AS). It has been suggested that rifaximin have the ability to modulate the gut bacterial communities, prevent inflammatory response, and modulate gut barrier function. The goal of this work is to evaluate the protective effects of rifaximin in fighting AS and to elucidate the potential underlying mechanism. Rifaximin were administered to the proteoglycan (PG)-induced AS mice for 4 consecutive weeks. The disease severity was measured with the clinical and histological of arthritis and spondylitis. Intestinal histopathological, pro-inflammatory cytokine levels and the intestinal mucosal barrier were evaluated. Then, western blot was performed to explore the toll-like receptor 4 (TLR-4) signal transducer and NF-κB expression. Stool samples were collected to analyze the differences in the gut microbiota via next-generation sequencing of 16S rDNA. We found that rifaximin significantly reduced the severity of AS and resulted in down-regulation of inflammatory factors, such as TNF-α, IL-6, IL-17A, and IL-23. Meanwhile, rifaximin prevented ileum histological alterations, restored intestinal barrier function and inhibited TLR-4/NF-κB signaling pathway activation. Rifaximin also changed the gut microbiota composition with increased phylum ratio, as well as selectively promoting some probiotic populations, including . Our results suggest that rifaximin suppressed progression of AS and regulated gut microbiota in AS mice. Rifaximin might be useful as a novel treatment for AS.

PurposeKnowledge of interlaminar space is important for undertaking percutaneous endoscopic discectomy via an interlaminar approach (PED-IL). However, dynamic changes in the lumbar interlaminar space and the spatial relationship between the interlaminar space and intervertebral disc space (IDS) are not clear. The aim of this study was to anatomically clarify the changes in interlaminar space height (ILH) and variation in distance between the two spaces during flexion–extension of the lumbar spine in vitro.MethodsFirst, we used a validated custom-made loading equipment to obtain neutral, flexion, and extension 3D models of eight lumbar specimens through 3D reconstruction software. Changes in ILH (ILH, IL-yH, IL-zH) and distances between the horizontal plane passing through the lowest edge of the lamina of the superior lumbar vertebrae and the horizontal plane passing through the lowest position of the trailing edge of the same-level IDS (DpLID) at L3/4, L4/5 and L5/S1 were examined on 3D lumbar models.ResultsWe found that ILH was greater at L4/5 than at L3/4 and L5/S1 in the neutral position, but the difference was not significant. In the flexion position, ILH was significantly more than that in neutral and extension positions at L3/4, L4/5, and L5/S1. There were significantly more DpLID changes from neutral to flexion than that from neutral to extension at all levels (L3/4, L4/5, L5/S1).ConclusionThese findings demonstrated level-specific changes in ILH and DpLID during flexion–extension. The data may provide a better understanding of the spatial relationship between lumbar interlaminar space and IDS, and aid the development of segment-specific treatment for PED-IL.

Summary of backgroundPseudoaneurysms of the lumbar arteries following transforaminal lumbar interbody fusion (TLIF) are rare postoperative complications that usually occur around the transverse process. However, there are few detailed descriptions of the transverse branch and other branches of the dorsal branches at the L1–L4 disks.Study designTen adult embalmed cadavers were anatomically studied.ObjectivesThe purposes of the study were to describe the vascular distribution of the dorsal branches, especially the transverse branches, at the L1–L4 levels and provide information useful for TLIF.MethodsTen embalmed cadavers studied after their arterial systems were injected with red latex. The quantity, origin, pathway, distribution range and diameter of the branches were recorded and photographed.ResultsThe transverse branch appeared in all 80 intervertebral foramina. The transverse branch was divided into 2 types: In type 1, the arteries divided into superior branches and inferior branches; the arteries in type 2 divided into 3 branches (superior, intermedius and inferior branches).ConclusionsThe transverse branches of the dorsal arteries are common structures from L1 to L4, and 2 types of transverse branches were found. A thorough understanding of the dorsal branches, especially the transverse branches of the lumbar artery, may be very important for reducing both intraoperative bleeding during the surgery and the occurrence of pseudoaneurysms after transforaminal lumbar interbody fusion.

Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts, blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors. Due to these adverse effects, preosteoblast senescence is a crucial target for the treatment of age-related bone loss; however, the underlying mechanism remains unclear. We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model. Mechanistically, mTORC1 induced a change in the membrane potential from polarization to depolarization, thus promoting cell senescence by increasing Ca influx and activating downstream NFAT/ATF3/p53 signaling. We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts. Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα, whereas its permeability to Na was found to be gated by protein kinase A (PKA)-induced phosphorylation. Prosenescent stresses increased the permeability of Scn1a to Na by suppressing PKA activity and induced depolarization in preosteoblasts. Together, our findings identify a novel pathway involving mTORC1, Scn1a expression and gating, plasma membrane depolarization, increased Ca influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence. Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.

Purpose To investigate the efficacy and safety of allograft and hydroxyapatite (HA) as substitutes for autograft in anterior cervical discectomy and fusion (ACDF). Methods In this study, 49 patients (80 segments) treated with ACDF were included and allocated into three groups [group A, autogenous iliac bone, n = 18; group B, allogeneic bone, n = 16; group C, HA, n = 15]. The clinical efficacy and fusion status were compared among each group. Complications were recorded in detail, and the Bazaz classification and Voice Handicap Index-10 (VHI-10) were used to detect dysphagia and dysphonia. Results Patients exhibited similar clinical efficacy among the groups during the final follow-up. All patients in groups A and B achieved fusion compared to only 73.3% of patients in group C. Groups A and B had similar fusion score, both of which greater than that of group C. No cage subsidence was observed in group A; however, 6.3% of patients in group B and 53.3% in group C had cage subsidence. Two patients in group A (11.1%) had persistent pain at the donor site. One patient in group B had dysphagia and dysphonia (6.3%), while one patient in group C had dysphonia (6.7%). Conclusion In ACDF, the autogenous iliac bone was the most ideal bone graft. The allogeneic bone was an acceptable substitute but risked cage subsidence and dysphagia. HA had a much lower fusion rate and a high risk of cage subsidence. Better substitutes should be further explored for ACDF.

Ankylosing spondylitis is a chronic, progressive disease, and its treatment is relevant to the gut microbiota. Anti‐tumor necrosis factor‐alpha (anti‐TNF‐α) therapy alters the gut microbiota in many diseases, including inflammatory bowel disease. However, little is known about the effect of TNF‐α blocker treatment on the gut microbiota in ankylosing spondylitis. Herein, the effect of a TNF‐α blocker on the gut microbiota in proteoglycan‐induced arthritis was investigated. Proteoglycan‐induced mice were treated with an rhTNFR:Fc solution of etanercept (5 µg/g) for 4 weeks. rhTNFR:Fc treatment attenuated the arthritis incidence and severity of arthritis in the proteoglycan‐induced mice and decreased inflammation in the ankle joints and ameliorated ileal tissue destruction. Moreover, high gut permeability occurred, and zonula occludens‐1 and occludin protein levels were reduced in proteoglycan‐induced mice. These levels were significantly restored by the administration of rhTNFR:Fc. The serum TNF‐α and IL‐17 levels were also decreased. In addition, flora analysis via 16S rDNA high‐throughput sequencing revealed that rhTNFR:Fc treatment restored the gut microbiota composition to a composition similar to that in control mice. In conclusion, anti‐TNF‐α therapy attenuated proteoglycan‐induced arthritis progression and modulated the gut microbiota and intestinal barrier function. These results provide new insights for anti‐TNF‐α therapy strategies via regulating the gut microbiota in ankylosing spondylitis. Anti‐TNF alpha therapy attenuated the incidence and severity of ankylosing spondylitis in mice. Anti‐TNF alpha therapy modulated gut microbiota of ankylosing spondylitis in mice. Anti‐TNF alpha therapy repaired the gut barrier function of ankylosing spondylitis in mice.