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The mammalian/mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that integrates inputs from nutrients and growth factors to control many fundamental cellular processes through two distinct protein complexes mTORC1 and mTORC2. Recent mouse genetic studies have established that mTOR pathways play important roles in regulating multiple aspects of skeletal development and homeostasis. In addition, mTORC1 has emerged as a common effector mediating the bone anabolic effect of Igf1, Wnt and Bmp. Dysregulation of mTORC1 could contribute to various skeletal diseases including osteoarthritis and osteoporosis. Here we review the current understanding of mTOR signaling in skeletal development and bone homeostasis, as well as in the maintenance of articular cartilage. We speculate that targeting mTOR signaling may be a valuable approach for treating skeletal diseases.

Preosteoblasts are precursor cells that are committed to the osteoblast lineage. Differentiation of these cells to mature osteoblasts is regulated by the extracellular factors and environmental cues. Recent studies have implicated mTOR signaling in the regulation of osteoblast differentiation. However, mTOR exists in two distinct protein complexes (mTORC1 and mTORC2), and the specific role of mTORC1 in regulating the progression of preosteoblasts to mature osteoblastis still unclear. In this study, we first deleted Raptor, a unique and essential component of mTORC1, in primary calvarial cells. Deletion of Raptor resulted in loss of mTORC1 but an increase in mTORC2 signaling without overtly affecting autophagy. Under the osteogenic culture condition, Raptor-deficient cells exhibited a decrease in matrix synthesis and mineralization. qPCR analyses revealed that deletion of Raptor reduced the expression of late-stage markers for osteoblast differentiation (Bglap, Ibsp, and Col1a), while slightly increasing early osteoblast markers (Runx2, Sp7, and Alpl). Consistent with the findings in vitro, genetic ablation of Raptor in osterix-expressing cells led to osteopenia in mice. Together, our findings have identified a specific role for mTORC1 in the transition from preosteoblasts to mature osteoblasts.

Percutaneous vertebroplasty (PVP) has been used widely to treat osteoporotic vertebral compression fractures (OVCFs). However, it has many disadvantages, such as excessive radiation exposure, long operation times, and high cement leakage rates. This study was conducted to explore the clinical effects and safety of the use of a three-dimensional (3D)-printed body-surface guide plate to aid PVP for the treatment of OVCFs. This prospective cohort study was conducted with patients with OVCFs presenting between October 2020 and June 2021. Fifty patients underwent traditional PVP (group T) and 47 patients underwent PVP aided by 3D-printed body-surface guide plates (3D group). The following clinical and adverse events were compared between groups: the puncture positioning, puncture, fluoroscopy exposure and total operation times; changes in vertebral height and the Cobb angle after surgery relative to baseline; preoperative and postoperative visual analog scale and Oswestry disability index scores; and perioperative complications (bone cement leakage, neurological impairment, vertebral infection, and cardiopulmonary complications. The puncture, adjustment, fluoroscopy, and total operation times were shorter in the 3D group than in group T. Visual analog scale and Oswestry disability index scores improved significantly after surgery, with significant differences between groups (both p < 0.05). At the last follow-up examination, the vertebral midline height and Cobb angle did not differ between groups. The incidence of complications was significantly lower in the 3D group than in group T (p < 0.05). The use of 3D-printed body-surface guide plates can simplify and optimize PVP, shortening the operative time, improving the success rate, reducing surgical complications, and overall improving the safety of PVP.

As the most prevalent sustained cardiac arrhythmia, atrial fibrillation (AF) remains incompletely characterized in terms of its molecular drivers. This investigation seeks to systematically identify critical molecular determinants and delineate their regulatory circuitry governing AF pathogenesis. Using integrated transcriptomic and single-cell analyses, we identified ETV1 as a potential AF-associated regulator. Functional validation was performed through gain- and loss-of-function experiments in vitro and in vivo, combined with pharmacological modulation of the ERK1/2–RSK3 pathway and comprehensive cardiac phenotyping. ETV1 was found to be significantly overexpressed in cardiomyocytes from AF patients. Activation of the ERK1/2–RSK3–ETV1 axis induced hallmark AF features, including myocardial fibrosis, electrical remodeling, and calcium dysregulation. Inhibition or genetic ablation of ETV1 reversed these phenotypes and reduced AF susceptibility in vivo. Our findings identify ETV1 as a central regulator of AF pathogenesis, functioning through a self-reinforcing ERK1/2–RSK3–ETV1 signaling loop. Targeting this upstream axis offers a promising therapeutic strategy distinct from conventional downstream modulation approaches.

Osterix (Osx or Sp7) is a zinc-finger-family transcriptional factor essential for osteoblast differentiation in mammals. The Osx-Cre mouse line (also known as Osx1-GFP::Cre) expresses GFP::Cre fusion protein from a BAC transgene containing the Osx regulatory sequence. The mouse strain was initially characterized during embryogenesis, and found to target mainly osteoblast-lineage cells. Because the strain has been increasingly used in postnatal studies, it is important to evaluate its targeting specificity in mice after birth. By crossing the Osx-Cre mouse with the R26-mT/mG reporter line and analyzing the progenies at two months of age, we find that Osx-Cre targets not only osteoblasts, osteocytes and hypertrophic chondrocytes as expected, but also stromal cells, adipocytes and perivascular cells in the bone marrow. The targeting of adipocytes and perivascular cells appears to be specific to those residing within the bone marrow, as the same cell types elsewhere are not targeted. Beyond the skeleton, Osx-Cre also targets the olfactory glomerular cells, and a subset of the gastric and intestinal epithelium. Thus, potential contributions from the non-osteoblast-lineage cells should be considered when Osx-Cre is used to study gene functions in postnatal mice.

Background Percutaneous vertebroplasty (PVP) has been used widely to treat osteoporotic vertebral compression fractures (OVCFs). However, it has many disadvantages, such as excessive radiation exposure, long operation times, and high cement leakage rates. This study was conducted to explore the clinical effects and safety of the use of a three-dimensional (3D)-printed body-surface guide plate to aid PVP for the treatment of OVCFs. Methods This prospective cohort study was conducted with patients with OVCFs presenting between October 2020 and June 2021. Fifty patients underwent traditional PVP (group T) and 47 patients underwent PVP aided by 3D-printed body-surface guide plates (3D group). The following clinical and adverse events were compared between groups: the puncture positioning, puncture, fluoroscopy exposure and total operation times; changes in vertebral height and the Cobb angle after surgery relative to baseline; preoperative and postoperative visual analog scale and Oswestry disability index scores; and perioperative complications (bone cement leakage, neurological impairment, vertebral infection, and cardiopulmonary complications. Results The puncture, adjustment, fluoroscopy, and total operation times were shorter in the 3D group than in group T. Visual analog scale and Oswestry disability index scores improved significantly after surgery, with significant differences between groups (both p < 0.05). At the last follow-up examination, the vertebral midline height and Cobb angle did not differ between groups. The incidence of complications was significantly lower in the 3D group than in group T (p < 0.05). Conclusion The use of 3D-printed body-surface guide plates can simplify and optimize PVP, shortening the operative time, improving the success rate, reducing surgical complications, and overall improving the safety of PVP.

Significance Hedgehog (Hh) signaling is essential for embryonic bone formation in mammals. However, how Hh signaling executes the osteogenic function is not clear. We describe a positive feedback mechanism whereby Hh-Gli2 signaling induces expression of insulin-like growth factor 2 (Igf2), which signals via protein kinases mTORC2 and Akt to stabilize Gli2 and potentiate Hh induction of osteoblast differentiation. The Hh-Igf positive feedback loop may have general implications for Hh signaling in development and disease. Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.

Immunotherapy has revolutionized cancer treatment by leveraging the immune system’s innate capabilities to combat malignancies. Despite the promise of tumor antigens in stimulating anti-tumor immune responses, their clinical utility is hampered by limitations in eliciting robust and durable immune reactions, exacerbated by tumor heterogeneity and immune evasion mechanisms. Recent insights into the immunogenic properties of host homologous microbial antigens have sparked interest in their potential for augmenting anti-tumor immunity while minimizing off-target effects. This review explores the therapeutic potential of microbial antigen peptides in tumor immunotherapy, beginning with an overview of tumor antigens and their challenges in clinical translation. We further explore the intricate relationship between microorganisms and tumor development, elucidating the concept of molecular mimicry and its implications for immune recognition of tumor-associated antigens. Finally, we discuss methodologies for identifying and characterizing microbial antigen peptides, highlighting their immunogenicity and prospects for therapeutic application.

Objective To assess the biomechanical effect of transforaminal endoscopic lumbar discectomy combined with spinal dynamic stabilization system (TELD-SDSS) on the adjacent segments using three-dimensional finite element (3D-FE) analysis, providing reference data for the optimization of surgical approaches for giant lumbar disc herniation (GLDH). Methods A 3D-FE model of L3–S1 was constructed based on imaging data and validated against well-established in-vitro biomechanical data. Surgical FE models representing TELD, TELD-SDSS, and posterior lumbar interbody fusion (PLIF) were reconstructed. The risk of adjacent segment degeneration (ASD) was evaluated by comparing adjacent-segment biomechanical parameters under various loading directions using hybrid testing methods. Results Compared with the FE model, the PLIF model showed the largest increases in adjacent-segment range of motion, intradiscal pressure, endplate Von Mises stress, and annulus fibrosus shear stress under flexion, extension, lateral bending, and rotational loading. The TELD-SDSS model showed lesser increases, and results for the TELD models did not differ significantly. Conclusions The study findings suggest that TELD with limited foraminoplasty and large annuloplasty has no significant impact on the occurrence of ASD. Although TELD-SDSS application alters the biomechanical environment of the adjacent segments, it has potential biomechanical advantages over PLIF in the mitigation of ASD occurrence.

WNT signaling has been implicated in both embryonic and postnatal bone formation. However, the pertinent WNT ligands and their downstream signaling mechanisms are not well understood. To investigate the osteogenic capacity of WNT7B and WNT5A, both normally expressed in the developing bone, we engineered mouse strains to express either protein in a Cre-dependent manner. Targeted induction of WNT7B, but not WNT5A, in the osteoblast lineage dramatically enhanced bone mass due to increased osteoblast number and activity; this phenotype began in the late-stage embryo and intensified postnatally. Similarly, postnatal induction of WNT7B in Runx2-lineage cells greatly stimulated bone formation. WNT7B activated mTORC1 through PI3K-AKT signaling. Genetic disruption of mTORC1 signaling by deleting Raptor in the osteoblast lineage alleviated the WNT7B-induced high-bone-mass phenotype. Thus, WNT7B promotes bone formation in part through mTORC1 activation.