Mechanical unloading that results from aging, prolonged bed rest, or spaceflight leads to disuse osteoporosis (DOP), a significant public health concern. However, the mechanisms underlying this condition, as well as effective therapeutic strategies, remain incompletely defined. In this study, significant bone deterioration, increased osteoclast activation, and upregulation of the PI3K/AKT/NF-κB signaling cascade were observed in femoral specimens from hindlimb suspension (HLS) mice, a well-established DOP model. Phloretin, a naturally occurring flavonoid with notable antioxidant and anti-inflammatory activities, has shown anti-osteoclastogenic effects in chemically induced models. Nevertheless, its therapeutic efficacy and direct molecular targets in mechanical unloading-induced bone loss, a condition characterized by a distinct pathophysiology, remain largely undefined. Herein, we demonstrated that phloretin markedly suppressed osteoclastogenesis, attenuated excessive bone resorption and effectively counteracted bone loss in the hindlimb-unloading murine model. Complementing these in vivo findings, primary osteoclast cultures revealed that phloretin reduced osteoclast formation and activity by inhibiting the PI3K/AKT/NF-κB signaling axis. Importantly, pharmacological activation of the PI3K pathway with 740 Y-P significantly reduced Phloretin's inhibitory effects on osteoclast differentiation and bone protection, confirming that this pathway is the primary regulatory target. Unlike general anti-resorptive agents, phloretin specifically addresses the PI3K-mediated signaling activation triggered by mechanical unloading. Our findings provide robust evidence for the application of phloretin as a targeted therapy for disuse-related skeletal disorders.

Magnesium is the fourth most abundant inorganic element in the human body, critical for skeletal development. Biodegradable magnesium materials have excellent biocompatibility and unique bioactivity, widely studied in orthopedics. Thus, we used a rat Achilles tendon injury model to evaluate magnesium foil s effects on adhesion, inflammation, and healing. Results showed magnesium foil effectively reduced peritendinous adhesion, alleviated local inflammation, improved collagen organization, and enhanced biomechanical properties, supporting physiological repair. In conclusion, biodegradable magnesium foil is a promising anti-adhesion barrier for tendon injury treatment.

Early weight-bearing (EWB) following ankle fracture surgery represents a paradigm shift from traditional rehabilitation protocols. This systematic review and meta-analysis evaluated the efficacy and safety of early versus delayed weight-bearing following operative treatment of ankle fractures. We systematically searched six databases (PubMed, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL, PEDro) from January 2015 to February 2025. Twelve studies (1,847 participants) comparing early (≤ 2 weeks) versus delayed weight-bearing protocols were included. Primary outcomes included functional scores, pain, range of motion, and complications. Random-effects meta-analyses used standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes. Early weight-bearing demonstrated significant advantages in pain reduction (SMD: +0.32, 95

IntroductionAdipose-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative therapies, but their clinical application is limited by cellular aging. This study investigated the effects of hydrogen on ADSC senescence and myogenic differentiation, along with the underlying molecular mechanisms.MethodsADSCs were treated with hydrogen gas. Senescence was assessed using β-galactosidase staining, proliferation assays, measurements of mitochondrial oxidative stress, and protein expression analysis. Differentiation capacity was evaluated through MyHC immunofluorescence, MYOD expression profiling, and quantification of myogenic regulatory factors. Additionally, the key molecular pathway of hydrogen's action was investigated by pharmacologically inhibiting PRDX6.ResultsThe findings showed that hydrogen treatment reduced senescence and increased differentiation capacity, as evidenced by higher proportions of MyHC-positive cells, increased myogenin levels, and decreased Muscle RING finger protein1 (MuRF1) expression. Molecular investigations revealed activation of the PRDX6/SIRT1/PGC-1α axis, accompanied by elevated NQO-1 expression. Importantly, pharmacological inhibition of PRDX6 largely eliminated the protective effects of hydrogen on cellular aging, disrupted differentiation, and caused mitochondrial dysfunction.DiscussionThese results suggest that hydrogen can regulate ADSC behavior via PRDX6-driven activation of SIRT1/PGC-1α signaling, offering potential approaches to improve stem cell quality for regenerative medicine.

Osteoarthritis (OA) is a chronic degenerative joint disease predominantly observed in middle-aged and elderly individuals, with its complex pathological mechanisms significantly affecting patients’ quality of life. Due to the absence of effective treatment strategies, there has been a growing emphasis on molecular targeted therapies for OA. As a critical transcription factor, Forkhead box O3a (FoxO3a) plays a vital role in physiological processes such as cell differentiation, survival, and apoptosis. The activity of FoxO3a is modulated by post-translational modifications, including phosphorylation and acetylation, as well as by various signaling pathways. Recent studies have demonstrated that FoxO3a significantly influences the onset and progression of OA by regulating multiple processes in chondrocytes, including redox homeostasis, inflammatory response, cell survival, and matrix degradation. Its active expression presents potential value for the prevention and treatment of OA. This article reviews the research advancements regarding the role of FoxO3a in the pathogenesis of OA, emphasizing its effects on physiological activities such as oxidative stress and regulatory mechanisms in chondrocytes, with the aim of refining the understanding of OA pathogenesis and providing new insights for its prevention and treatment.

Functional repair of the tendon-bone interface poses significant challenges in clinical practice; furthermore, identifying methods to enhance healing at enthesis is a central concern in regenerative medicine. The application of stem cells in the healing process of interface injuries is widespread; however, direct injection of stem cells into this interface leads to significant losses of many stem cells. Oxidative stress significantly influences interface repair, and the role of selenium in mitigating oxidative stress and regulating inflammation has been demonstrated. This study utilised gelatine methacrylate (GelMA) as a stem cell transporter, while porous Se@SiO2 nanoparticles (Se@SiO2 NPs) were incorporated to change the interface microenvironment and facilitate the repair of the tendon-bone interface. Oxidative stress effects were analysed using flow cytometry, immunofluorescence staining, and qRT-PCR. The repair of the enthesis was assessed using histological staining, biomechanical evaluation, and MRI. Se@SiO2 NPs significantly reduced the expression of inflammation-related markers in an in vitro oxidative stress model. Additionally, porous selenium nanocomposite hydrogels loaded with adipose stem cells were implanted into the rat tendon-bone interface. At eight weeks following the procedure, the enthesis exhibited superior collagen fibre continuity and orientation, enhanced bone and fibrocartilage production, and biomechanical functions that were substantially greater than those of the comparison group. This study demonstrates that porous Se@SiO2 NP composite hydrogels with antioxidant and anti-inflammatory properties provide a supportive environment for transplanted stem cells and promote tissue repair.

The dynamic production and clearance of senescent osteoblasts affects bone homeostasis and health. However, the relationship between senescent osteoblasts and the immune system remains unclear. Here, a landscape of the interaction between immune cells and osteoblasts through spatial analysis of the bone microenvironment is presented. Sirtuin 1 (SIRT1), a longevity gene, regulates bone mass maintenance through a mechanism involving osteoblast-CD4+ cytotoxic T lymphocyte (CTL) crosstalk. In the osteoblastic niche, SIRT1 promotes the secretion of crucial chemokines, such as C-C motif chemokine ligand 3 (CCL3), C-C motif chemokine ligand 5 (CCL5), and C-X-C motif chemokine ligand 10 (CXCL10), by upregulating dishevelled-associated activator of morphogenesis 2 (DAAM2) through the acetylation of enhancer of zeste homolog 2 (EZH2), activating and recruiting CD4+ CTLs that eliminate senescent osteoblasts in a major histocompatibility complex class II (MHC-II)-dependent manner, slowing the bone ageing process and ameliorating osteoporosis. DAAM2 serves as a pivotal downstream effector for SIRT1 to exert immune-regulatory effects in the bone microenvironment; thus, targeting DAAM2 can treat osteoporosis by increasing CD4+ CTL responses. These results will facilitate the development of customised therapies targeting senescent osteoblasts to maintain bone health.

Thrombospondin 2 (THBS2), belongs to the platelet reactive protein family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell–cell and cell–matrix interactions. Recently, a sequencing study suggested that THBS2 may be involved in the progression of spinal cord injury (SCI). This study aims to explore the expression pattern and the possible role of THBS2 in SCI, and the signaling pathway that THBS2 mainly relies on for its function. In the present study, we collected clinical samples and established both a rat model and a cell model of SCI. The expression of THBS2 in the model and clinical samples was detected by western blot assay/immunofluorescence and RT-qPCR. After establishing the rat SCI model, Basso-Beattie-Bresnahan (BBB) behavioral scores were used to detect changes in motor function. Spinal cord water content measurement was used to assess spinal cord edema in rats. To investigate the effect of THBS2 on SCI models, THBS2- expressing plasmid/THBS2-siRNA/SB 202190 (p38MAPK pathway inhibitor)/p38 agonist was applied to the rat SCI models and PC12 cell SCI model. Hematoxylin–eosin (H E) staining was used to detect spinal cord lesions in rats. TUNEL and flow cytometry (FCM) assays were conducted to determine the apoptosis level, both in vivo and in vitro. Cell viability was determined by CCK-8 assay. Changes in inflammatory factor (TNF-α, IL-1β and IL-6) levels in models were quantified by enzyme linked immunosorbent assay (ELISA). Finally, p38MAPK signaling pathway-related proteins and apoptosis-related proteins were detected by western blot assay. The expression of THBS2 showed a gradual increase and decrease process after SCI, with the most significant increase observed in the mid-phase of SCI. THBS2-expressing plasmid and SB 202190 significantly increased BBB score scores, while decreased spinal cord water content. Also, the H E staining results suggested that overexpression of THBS2-plasmid and SB 202190 could inhibit spinal cord lesions. THBS2 and SB 202190 treatment significantly enhanced the cell ability of LPS-induced PC12 cells. In addition, THBS2-expressing plasmid and SB 202190 inhibited the level of apoptosis and suppressed the secretion of inflammatory factors in both in vivo and in vitro models. Moreover, overexpression of THBS2 inhibited the activation of the p38MAPK signaling pathway in SCI models, and p38 agonist reversed the protective effects of THBS2-plasmid on SCI rats and LPS-induced PC12 cells. In addition, THBS2 down-regulation further promote LPS-induced apoptosis and inflammatory response in PC12 cells. THBS2 was highly expressed in SCI, and overexpression of THBS inhibited the activation of the MAPK signaling pathway and thus protects against SCI.

BACKGROUND:The ultrastructure of the tendon-bone interface (TBI) is inherently complex. After arthroscopic reconstruction, it is often replaced by disorganized scar tissue, which increases the risk of re-tearing.Stem cell therapies offer a promising approach to regenerate the original tissue structure and enhance the healing environment. The effectiveness of these therapies depends on understanding the localization, proliferation, and overall behavior of the implanted stem cells. This study aimed to track the distribution of stem cells in a rat model of rotator cuff injury using Magnetic Resonance Imaging (MRI) and superparamagnetic iron oxide nanoparticles (SPIO) and to evaluate the mechanisms and therapeutic effects of stem cell therapy. METHODS:Adipose-derived mesenchymal stem cells (ADSCs) were isolated and expanded, then labeled with SPIO at an optimized concentration. The visibility of these labeled cells was assessed via MRI, along with evaluations of their viability, potential toxicity, and migration capacity in vitro.For the in vivo study, rats with rotator cuff tears were divided into two groups: a control group that received a PBS injection, and a treatment group that received SPIO-labeled ADSCs (designated as S-A). MRI scans were conducted at 1, 2, and 4 weeks post-surgery, followed by histological analysis after the rats were euthanized. At 8 weeks post-surgery, rats were sacrificed, and their shoulder joints were analyzed biomechanically and histologically to assess the overall treatment efficacy. RESULTS:SPIO nanoparticles were successfully incorporated into ADSCs, and MRI imaging demonstrated that these SPIO-labeled cells significantly enhanced MRI contrast without affecting cell viability, proliferation, or migration ability. Both MRI and histological analyses confirmed that the implanted stem cells survived and remained localized for at least two weeks. Further histological and biomechanical evaluations indicated that the stem cells facilitated the repair of the TBI. This repair process appeared to be mediated by an increase in M2 macrophage activity within the injured tissue, promoting improved local healing conditions. CONCLUSION:This study confirms that labeling ADSCs with SPIO nanoparticles is an effective method for tracking these cells in vivo using MRI, providing a non-invasive approach to monitor the repair of injured TBI. Moreover, the localized survival of transplanted stem cells supports their role in enhancing TBI repair by modulating the local inflammatory response.

The inhibition of ferroptosis, a widespread form of nonapoptotic cell death, is considered a promising therapeutic approach for osteoarthritis (OA). Human amniotic epithelial stem cells (hAESCs) maintain multipotent differentiation potential, no tumorigenicity, low immunogenicity, and anti-inflammatory properties, rendering them highly biocompatible stem cells. Exosomes (Exo) are vesicular carriers for intercellular communication that participate importantly in regulating disease progression through paracrine signaling. In our study, under inflammatory stress conditions, actin alpha 2, smooth muscle antisense RNA1 (ACTA2-AS1) transcription was up-regulated in hAESCs, further delivered to chondrocytes via hAESC-derived Exo. Subsequently, ACTA2-AS1 could suppress ferroptosis in chondrocytes by facilitating the degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), a key regulator of ferroptosis, thereby modulating the progression of OA. In conclusion, for the first time, this study demonstrates the modulatory role of hAESC ACSL4 expression by releasing ACTA2-AS1-enriched Exo, leading to inhibited ferroptosis in chondrocytes and ultimately ameliorating OA progression. Thus, targeting Exo-mediated communication may offer novel therapeutic approaches for addressing OA linked to iron metabolism irregularities.

Implant-related infections (IRIs) pose a major challenge in orthopedic applications due to the persistence of biofilms, which are highly resistant to conventional antibiotics. This study introduces oxygen vacancy-engineered Zn-Fe spinel nanoparticles as microwave-responsive antibacterial agents. The oxygen vacancies in the spinel structure enhance reactive oxygen species (ROS) generation under microwave irradiation, providing a dual-mode antibacterial mechanism of thermal and oxidative stress. Zn-Fe spinel nanoparticles were synthesized using a sol-gel method and evaluated for their antibacterial efficacy against Staphylococcus aureus biofilms. Under microwave irradiation, the Zn-Fe spinel demonstrated significant biofilm disruption and bacterial eradication. Mechanistic studies revealed that oxygen vacancies promoted ROS generation, leading to bacterial membrane damage. In vivo experiments using a mouse infection model confirmed the material's antibacterial efficacy and biocompatibility, with no observed toxicity. This study highlights the potential of oxygen vacancy-enhanced Zn-Fe spinel as a microwave-assisted, antibiotic-free strategy for treating deep-seated infections associated with orthopedic implants.

Purpose Infrapatellar pole fractures are challenging injuries that require appropriate treatment to ensure optimal functional outcomes. This study aimed to introduce the application of the Suture Bridge technique using the 5-Ethibond for the treatment of infrapatellar patella fracture. Methods Five cases of infrapatellar pole fracture that were treated at our institution between February 2020 and September 2021. The patients included one male and four females, with an average age of 66 years (range: 60-77 years). All patients were treated with the Suture Bridge technique using the 5-Ethibond to preserve the infrapatellar pole. Results The average operative time was 64 min (range: 50-80 min). The average blood loss during surgery was 51 mL (range: 40-60 mL). All cases demonstrated fracture healing at an average of 10 weeks (range 8-12) after surgery. The patients were followed up for an average period of 14.8 months (8-22). No wound infection or second displacement of fracture fragment was found. Full range of motion was restored in all patients within 12-14 weeks after surgery. None of the patients complained of anterior knee pain. Conclusions Based on the findings of the study, it appears that the Suture Bridge technique using 5-Ethibond is a promising and viable option for the treatment of infrapatellar pole fractures.

Objectives:Investigating the impact of cadmium (Cd) on annulus fibrosus (AF) cells and its potential mechanism was the purpose of the current study.Materials and Methods:Cd was cultivated in different concentrations (0, 1, 5, 10, and 20 μM) on AF cells and the potential effects of the metal were assessed. Using the CCK-8 method, cell viability and proliferation were identified. Using transcriptome analysis, the annulus fibrosus cells were sequenced both with and without cadmium chloride. The EdU method was used to determine the rate of cell proliferation; senescence-associated β-galactosidase (SA-β-Gal) staining was used to determine the number of positive cells; and western blot, RT-PCR, and immunofluorescence were used to determine the protein and mRNA expression of senescence-associated proteins (p16, p21, and p53) and c-Jun N-terminal kinase (JNK).Results:According to the findings, Cd has the ability to increase the production of senescence-associated genes (p16 and p21) and senescence-associated secreted phenotype (SASP), which includes IL-1β and IL-6. Through the JNK/p53 signal pathway, Cd exposure simultaneously accelerated AF cell senescence and promoted SASP. Following JNK inhibitor (SP600125) treatment, the expression of p53, JNK, and senescence-associated indices were all down-regulated.Conclusion:By activating the JNK/p53 signaling pathway, Cd can induce oxidative stress damage and AF cell senescence. These findings could provide a new approach for treating and preventing intervertebral disc degeneration (IVDD) caused by Cd exposure.

Objective: To compare the clinical efficacy of artificial total hip arthroplasty(THA) for femoral neck fracture between direct anterior approach(DAA) in lateral position and posterior lateral approach(PLA). Methods: Comparison of 200 cases of patients who underwent THA collected between September 2019 and August 2021 was done. Incision length, intraoperative bleeding, operative time, difference in postoperative haemoglobin from preoperative levels, length of hospital stay, postoperative time to get off the floor, visual analogue score (VAS) for pain, preoperative and postoperative Harris scores for the hip, and measurements of the acetabular abduction angle and anterior acetabular tilt angle at 6 months postoperatively were collected, and all the cases were followed up for at least 2 years. Results: Compared with the PLA group, the DAA group had a shorter incision length, less intraoperative blood loss, less postoperative haemoglobin reduction compared with the preoperative period, a shorter hospital stay and an earlier first time to get off the floor after surgery, however, the comparison of operative times was not statistically significant; Patients in the DAA group had a lower VAS in the early postoperative period compared to PLA; Patients in the DAA group had higher hip Harris scores at 6 weeks and 6 months postoperatively; There was no significant difference in acetabular abduction angle and acetabular anterior tilt angle between the two groups at 6 months postoperatively. Conclusion: Compared to PLA, DAA in THA is minimally invasive, has less pain, less bleeding, earlier time out of bed, shorter hospital stay, better early hip function, faster rehabilitation, and better joint stability.

BACKGROUND:Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment.METHODS:In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds.RESULTS:Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein.CONCLUSIONS:With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.

Osteomyelitis, a grave deep tissue infection primarily caused by Staphylococcus aureus, results in serious complications such as abscesses and sepsis. With the incidence from open fractures exceeding 30% and prevalent antibiotic resistance due to extensive treatment regimens, there's an urgent need for innovative, antibiotic-free strategies. Photothermal therapy (PTT) and photodynamic therapy (PDT) renowned for generating localized reactive oxygen species (ROS), face limitations in penetration depth. To overcome this, our method combines the deep penetration attributes of medical microwaves (MW) with the synergistic effects of the ZnO/ZrO2 solid solution. Comprehensive in vitro and in vivo evaluations showcased the solid-solution's potent antibacterial efficacy and biocompatibility. The ZnO/ZrO2 solid solution, especially in a 7:3 molar ratio, manifests superior microstructural characteristics, optimizing MW-assisted therapy. Our findings highlight the potential of this integrated strategy as a promising avenue in osteomyelitis management.

Abstract During ageing, the dynamic balance between the production and clearance of senescent osteoblasts affects bone homeostasis and health. However, the relationship between senescent osteoblasts and the immune system remains unclear. Here, we provide evidence that SIRT1, known as a longevity gene, could orchestrate bone mass maintenance through a novel mechanism involving osteoblast- CD4+ cytotoxic T lymphocyte (CTL) crosstalk. In the osteoblastic niche, SIRT1 promotes the secretion of key chemokines (e.g. CCL3, CCL5, and CXCL10) by upregulating DAAM2 through acetylation of EZH2 protein, thereby activating and recruiting CD4+ CTLs. Then, CD4+ CTLs eliminate senescent osteoblasts in an MHC-II-dependent manner, slowing the bone ageing process and effectively alleviating osteoporosis. This mechanism shows that DAAM2 is a pivotal downstream effector for SIRT1 to exert immune-regulatory effects in the bone microenvironment, and that targeting DAAM2 could accurately treat osteoporosis by increasing CD4+ CTL responses. This work enables a multi-perspective assessment of physiological bone senescence, paving the way for customised therapies targeting senescent osteoblasts to maintain bone health.

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

Ewing's sarcoma (EWS) is a highly aggressive malignant bone tumor primarily affecting adolescents and young adults. Despite the efficacy of chemoradiotherapy in some cases, the cure rate for patients with metastatic and recurrent disease remains low. Therefore, there is an urgent need for innovative therapeutic approaches to address the challenges associated with EWS treatment. Epigenetic regulation, a crucial factor in physiological processes, plays a significant role in controlling cell proliferation, maintaining gene integrity, and regulating transcription. Recent studies highlight the importance of abnormal epigenetic regulation in the initiation and progression of EWS. A comprehensive understanding of the intricate interactions between EWS and aberrant epigenetic regulation is essential for advancing clinical drug development. This review aims to provide a comprehensive overview of both epigenetic targets implicated in EWS, integrating various therapeutic modalities to offer innovative perspectives for the clinical diagnosis and treatment of EWS.