Objectives:This randomised controlled trial assessed the effectiveness and safety of weekly 56.5 μg teriparatide (SAL056) compared to alendronate in postmenopausal women in China with osteoporosis at high risk of fractures over 48 weeks. Methods:This phase 3, multicentre, randomised, open-label, active-controlled, parallel-group, non-inferiority trial enrolled postmenopausal women aged 45-80 years with osteoporosis at 37 centres in China. Participants were randomised (1:1) to receive either subcutaneous teriparatide 56.5 μg weekly or 70 mg oral alendronate weekly for 48 weeks, with the primary efficacy assessment at Week 48. Results:Between November 2021 and September 2023, 493 patients were enrolled (243 in the teriparatide group and 250 in the alendronate group). The primary endpoint, lumbar spine bone mineral density (BMD) at L1-L4, showed a significantly greater increase in the teriparatide group compared to the alendronate group at Week 48 (5.01% vs. 4.20%, mean difference 0.80%, P = 0.025). Sensitivity analysis confirmed these results. At Weeks 24 and 48, teriparatide also resulted in higher hip BMD than alendronate (1.50% vs. 1.46%, P > 0.05 and 3.27% vs. 1.67%, P < 0.001). Procollagen type 1 N-terminal propeptide (P1NP) levels in the teriparatide group increased transiently at Week 12, then declined toward baseline by Weeks 24 and 48, and a decrease in serum cross-linked c-terminal telopeptide of type I collagen (S-CTX) levels from baseline to the end of treatment. Meanwhile, in the alendronate (a typical bone resorption inhibitor) group, CTX level remained continuously suppressed from the baseline. Clinical fracture rates were lower in the teriparatide group than in the alendronate group at Weeks 24 (1.2% vs. 2.8%, P > 0.05) and 48 (1.7% vs. 4.0%, P > 0.05). Teriparatide was generally safe and well tolerated. Conclusions:Teriparatide (56.5 μg once weekly) was more effective than alendronate in treating postmenopausal osteoporosis with a high fracture risk, significantly increasing L1-L4 BMD over 48 weeks. It was safe, well tolerated, and had a safety profile similar to that of Teribone®. The translational potential of this article:This study demonstrates that once-weekly teriparatide significantly improves bone mineral density and reduces fracture risk in postmenopausal osteoporosis patients. As a patient-friendly alternative to daily injections, it may enhance adherence and inform clinical guidelines, representing a promising strategy for patients and healthcare systems.

Background Aseptic loosening (AL) is the primary cause of prosthesis failure after total joint replacement, which is triggered by wear particle-induced macrophage activation, excessive inflammatory factor secretion and subsequent periprosthetic osteolysis. MicroRNAs (miRNAs) act as key regulators of this pathological cascade, yet the specific functional miRNAs and their precise regulatory mechanisms remain incompletely clarified. Methods mRNA-seq and miRNA-seq were performed in titanium particle (TiPs)-stimulated macrophages to screen osteolysis-associated miRNAs, with expression validation conducted in clinical periprosthetic osteolytic tissues. In vitro functional and mechanistic assays were used to verify the miR-155-5p/Gas6/Axl regulatory axis, and a mouse calvarial osteolysis model was applied for in vivo validation. Macrophage membrane-camouflaged PLGA-PEI nanoparticles loaded with antagomir-155-5p (Anta-155@MNPs) were constructed, and their local therapeutic efficacy was evaluated in murine osteolysis models. Results miR-155-5p was significantly upregulated in both TiPs-stimulated macrophages and clinical periprosthetic osteolytic tissues. Functionally, miR-155-5p promoted Stat1/p65 phosphorylation, proinflammatory cytokine production and M1 macrophage polarization by inhibiting the Gas6/Axl pathway via dual mechanisms: Mafb-mediated Gas6 transcriptional repression and Adam10-dependent Axl cleavage inhibition. In vivo, this axis exacerbated TiPs-induced calvarial osteolysis, while local Anta-155@MNPs administration markedly mitigated bone resorption and tissue inflammation. Conclusion miR-155-5p drives TiPs-induced periprosthetic osteolysis via the Gas6/Axl signaling pathway, and targeted inhibition of miR-155-5p is a promising strategy to prevent artificial joint AL. The translational potential of this article This study identifies the miR-155-5p/Gas6/Axl axis as a novel therapeutic target for AL, and the targeted Anta-155@MNPs delivery system provides a feasible preclinical strategy for clinical translation to treat wear particle-induced osteolysis.

Total joint replacement (TJR) was one of the most revolutionary breakthroughs in joint surgery. The majority studies had shown that most implants could last about 25 years, anyway, there is still variation in the longevity of implants. In US, for all the hip revisions from 2012 to 2017 in the United States, 12.0% of the patients were diagnosed as aseptic loosening. Variable studies have showed that any factor that could cause a systemic or partial bone loss, might be the risk of periprosthetic osteolysis and aseptic loosening. Breast cancer is the most frequent malignancy in women, more than 2.1 million women were newly diagnosed with breast cancer, 626,679 women with breast cancer died in 2018. It's been reported that the mean incidence of THA was 0.29% for medicare population with breast cancer in USA, of which the incidence was 3.46% in Norwegian. However, the effects of breast cancer chemotherapy and hormonotherapy, such as aromatase inhibitors (AI), significantly increased the risk of osteoporosis, and had been proved to become a great threat to hip implants survival. In this case, a 46-year-old female undertook chemotherapy and hormonotherapy of breast cancer 3 years after her primary THA, was diagnosed with aseptic loosening of the hip prosthesis. Her treatment was summarized and analyzed. Breast cancer chemotherapy and hormonotherapy might be a threat to the stability of THA prosthesis. More attention should be paid when a THA paitent occurred with breast cancer. More studies about the effect of breast cancer treatments on skeleton are required.

Prosthetic wear particle-driven macrophage inflammation severely limits the long-term efficacy of total joint replacements by causing aseptic loosening. However, the specific mechanisms by which wear particles induce macrophage inflammation remain incompletely elucidated. Itaconic acid produced by the Krebs cycle is markedly up-regulated in TiPs-stimulated macrophages, which may modulate mitochondrial metabolism through protein itaconation or competitive inhibition. Here, using 4-OI, we demonstrate that itaconate functions as an endogenous metabolic regulator that suppresses SDH activity, thereby significantly inhibiting STING pathway activation. Moreover, 4-OI can alkylate STAT1, preventing its phosphorylation and relieving transcriptional repression of the mitochondrial transcription factor TFAM, which stabilizes mitochondrial homeostasis and attenuates macrophage inflammation. In a murine calvarial osteolysis model, 4-OI reversed bone destruction induced by TiPs and TFAM knockdown. Collectively, our findings establish itaconate as a critical endogenous metabolite that alleviates wear particle–mediated inflammation and osteolysis by reprogramming macrophage metabolism.

Aseptic loosening (AL) represents the primary cause of joint arthroplasty failure, which is predominantly triggered by chronic inflammatory reactions to prosthetic wear particles, with macrophages serving as the central effector cells. Accumulating evidence indicates that the crosstalk between endoplasmic reticulum stress and mitochondrial stress exacerbates macrophage-mediated inflammation; however, the core molecular regulators orchestrating this pathological cascade remain elusive. Herein, we investigated the functional role of the GATA6/DDX3X (DEAD-box helicase 3 X-linked) axis in titanium particle (TiP)-induced macrophage inflammatory responses and further explored the therapeutic potential of nanoparticle-loaded injectable hydrogels for AL. Specifically, a si-DDX3X-loaded nanoparticle hydrogel (si-DDX3X NPs@Hy) was fabricated and characterized, and its therapeutic efficacy was evaluated in vivo. Our results demonstrated that DDX3X expression was significantly up-regulated in both TiP-stimulated bone marrow-derived macrophages and periprosthetic tissues obtained from AL patients. Functional assays revealed that DDX3X promoted mitochondria-endoplasmic reticulum interplay, which in turn facilitated NLRP3 inflammasome assembly and subsequent interleukin-1β secretion. Mechanistically, GATA6 directly bound to the transcription start site of the DDX3X gene, thereby suppressing its transcriptional expression and abrogating DDX3X-mediated proinflammatory effects. The synthesized si-DDX3X NPs@Hy exhibited favorable physicochemical properties; local administration of this hydrogel markedly attenuated TiP-induced calvarial osteolysis in mice, accompanied by reduced osteoclastogenesis, proinflammatory cytokine production, and M1 macrophage polarization in the lesion microenvironment. Collectively, this study identifies the GATA6/DDX3X axis as a pivotal regulator of TiP-driven macrophage inflammation and validates the si-DDX3X NPs@Hy as a promising therapeutic strategy for targeting wear particle-induced inflammation, which holds great potential for improving the long-term prognosis of joint arthroplasty.

Total joint replacement represents the primary therapeutic approach for end-stage arthropathy, whereas aseptic loosening stands as the predominant cause of prosthesis failure. Particle disease, a cause of aseptic loosening, delineates a phenomenon wherein wear particles derived from the implant initiate a series of biological events, including inflammatory responses in macrophages, osteoclastogenesis, and suppression of osteoblastogenesis, ultimately resulting in periprosthetic osteolysis. Macrophage biomimetic nanoparticles offered promising platform for drug controlled-release with preeminent bio-compatibility. This research investigated the specific mechanism that miR-155-5p/Gas6/Axl axis regulated pro-inflammatory cytokines production and osteoblastic function and provided a novel therapeutic scheme which nanoparticles were coated with macrophage membrane and loaded with antagomir of miR-155-5p for aseptic loosening. mRNA-seq and miRNA-seq were conducted for gene enrichment and key gene selection. In vitro, RAW264.7 and MC3T3-E1 cells were cultured or co-cultured for titanium particles'(TiPs) stimulation. ELISA, western blot and flow cytometry were utilized for detection of inflammatory response. Osteoblastic function was measured by ALP and ARS staining. In vivo, mice calvaria osteolytic model were constructed for simulation of particle disease, microCT scanning and IHC staining of mice calviaria section were applied. The PLGA-PEI complex was constructed and antagomir were loaded. And the encapsulated nanoparticles were co-extruded with macrophage membrane to constructed intact biomimetic nanoparticle (Anta-155@MNP). In TiPs-stimulated macrophages, Axl expression was upregulated, and Gas6 was released extracellularly. This signaling cascade played a crucial role in instigating the inflammatory response, including activation of the NF-κB pathway and JAK-STAT pathway. The binding of miR-155-5p to the 3'UTR of Mafb and Adam10 mRNAs indirectly regulated the transcription of Gas6 and the shedding of Axl, leading to the generation of a soluble form of Axl that facilitated osteoblastogenesis. In vivo, the osteolytic model induced by TiPs further corroborated that the miR-155-5p/Axl signaling axis promoted sterile inflammation while concurrently suppressing osteoblastic differentiation. We prepared Anta-155@MNP and it displayed remarkable anti-osteolytic property by neutralizing cytokines, reducing inflammatory response and provoking osteoblastogenesis. Meanwhile, Anta-155@MNP alleviated TiPs-induced osteolysis and tissue inflammation in vivo. The miR-155-5p/Gas6/Axl axis plays a crucial role in the regulation of the osteolytic microenvironment. Anta-155@MNP holds promise as a targeted therapy for aseptic loosening with potential for translation into clinical applications.

Osteoporosis (OP) is a chronic skeletal disorder characterized by reduced bone mineral density and increased fracture risk, particularly from hip fractures linked to a 20%-24% increased mortality risk within the first year. Current therapies remained inadequate in addressing metabolic drivers, which prompted exploration of novel targets. Fabkin, a recently identified hormonal complex comprising fatty acid-binding protein 4 (FABP4), nucleoside diphosphate kinase (NDPK), and adenosine kinase (ADK), was implicated in metabolic and inflammatory signaling. It was suggested that Fabkin could promote Ca2+ influx and the release of inflammatory factors via the PKA pathway. However, its role in bone loss remained unclear. To investigate the role of Fabkin in OP, an ovariectomy (OVX)-induced murine model was used to simulate estrogen-deficient osteoporosis. FABP4-KO mice were generated to disrupt Fabkin formation, and bone microarchitecture was assessed using micro-CT and histological staining. Osteoclastogenesis assays in vitro were conducted using bone marrow-derived macrophages (BMDMs) treated with recombinant Fabkin components. Western blotting and RT-qPCR were performed to analyze key signaling pathways involved in osteoclast differentiation, particularly MAPK and NF-κB. Immunofluorescence analysis revealed an increase in Fabkin expression in the bone marrow of OVX mice. OVX-induced osteoporosis was significantly attenuated in FABP4-KO mice with higher BMD. TRAP staining showed a reduction in osteoclast numbers in FABP4-KO mice. In vitro, Fabkin treatment significantly enhanced osteoclast differentiation and bone resorption, whereas FABP4 deficiency inhibited osteoclast formation. Molecular analysis revealed that Fabkin promoted osteoclastogenesis via the RANKL-induced MAPK and NF-κB signaling pathways. These findings suggested that FABP4 might directly exacerbate osteoclastogenesis by acting as a Fabkin complex instead of a lipid regulator.

Ultrasonic radio frequency (RF) signal can be utilized in the diagnosis of osteoporosis (OP), thereby assisting healthcare professionals in enhancing the screening rates. However, the heterogeneity of the data collected from different centers can significantly affect the accuracy performance of the model, resulting in lower generalization performance in the target domain. We propose a knowledge-aware unsupervised domain adaptation network guided by knowledge perception that considers both common features and domain-specific features. We employ maximum mean discrepancy (MMD) loss to mitigate distribution discrepancies between various domains. In addition, major clinical risk factors (MCRF) are embedded in domain-specific feature extractors to better extract domain-invariant features. We collect in-house datasets from three distinct centers. Our model demonstrates promising results in both single-source and multi-source domain scenarios.

Small extracellular vesicles (sEVs) from human umbilical-cord-derived mesenchymal stem cells (UCMSCs) hold promise for cartilage regeneration in osteoarthritis (OA). However, their therapeutic effectiveness is significantly limited by rapid clearance through blood and lymphatic vessels in the synovial tissue after intra-articular injection. This study aimed to enhance the chondrocyte-targeting ability and improve the cartilage repair potential of UCMSC-derived sEVs by conjugating them with a chondrocyte-affinity peptide (CAP) using copper-free click chemistry. The targeting ability and therapeutic effects of these CAP-modified sEVs (CAP-sEVs) were evaluated in vitro and in vivo. CAP-sEVs exhibited enhanced chondrocyte targeting and greater retention within the articular cavity compared to nonmodified sEVs. In IL-1β-stimulated chondrocytes, CAP-sEVs significantly reduced the expression of matrix-degrading enzymes while increasing collagen type II synthesis, demonstrating superior therapeutic effects. Animal experiments further confirmed that CAP-sEVs had good biocompatibility, delayed articular cartilage degradation, and reduced subchondral bone loss in early stage OA. These findings suggest that CAP-sEVs represent a novel and promising strategy for OA treatment and provide an innovative drug delivery system for targeted cartilage therapy.

Purpose (the aim of the study): Macrophage activation plays a crucial part in synovial inflammation, a driving force in osteoarthritis (OA). Previous research has revealed that NOD2 attenuates OA by modulating macrophage activation, though the underlying mechanism remains unclear. This study aims to demonstrate whether NOD2 palmitoylation contributes to the modulation of macrophage activation and, if so, to uncover the regulatory mechanisms.

OBJECTIVE:This study aims to investigate the role of Denosumab and its downstream target ST18 in wear particle-induced macrophage inflammation and osteolysis, and to explore the underlying mechanisms involved in aseptic loosening (AL) of prosthetic joints. METHODS:Macrophages were stimulated with titanium particles (TiPs), and inflammatory responses were assessed using qRT-PCR, western blot, flow cytometry, and immunohistochemistry. Denosumab's effects on inflammation and osteolysis were evaluated with the same approaches. Potential targets of Denosumab were screened via online databases and validated by qRT-PCR and western blot. ST18 was modulated in macrophages using lentiviral overexpression and knockdown systems. A mouse calvarial model of TiPs-induced osteolysis was established, and the roles of Denosumab and ST18 were examined in vivo using micro-CT, H&E staining, and tartrate-resistant acid phosphatase (TRACP) staining. RESULTS:Denosumab suppressed TiPs-induced macrophage inflammation by inhibiting NF-κB signaling and M1 polarization. We identified ST18 as a direct target of Denosumab, whose expression was upregulated by TiPs but downregulated by Denosumab. Lentivirus-mediated ST18 knockdown markedly attenuated TiPs-induced inflammation, whereas ST18 overexpression exacerbated it. Further analysis revealed that ST18 interacts with PARP1. In vivo, Denosumab significantly alleviated TiPs-induced osteolysis in mouse calvaria, an effect that was reversed by ST18 overexpression. CONCLUSION:Denosumab attenuates TiPs-induced macrophage activation and osteolysis through suppression of the NF-κB pathway and M1 polarization, with ST18 serving as a key mediator. These findings highlight Denosumab as a promising therapeutic candidate for the prevention of prosthesis-related aseptic loosening.

Osteoarthritis (OA) is a degenerative joint disease associated with age, prominently marked by articular cartilage degradation. In OA cartilage, the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis. The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA. As age advances, mitochondrial function declines progressively, which leads to an imbalance in chondrocyte energy homeostasis, partially initiating the process of cartilage degeneration. Elevated oxidative stress, impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology, with mitochondrial DNA haplogroups, particularly haplogroup J, influencing OA progression. Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases, with triphenylphosphonium (TPP) emerging as the most widely utilized molecule. Other strategies encompass Dequalinium (DQA), the Szeto-Schiller (SS) tetrapeptide family, the KLA peptide, and mitochondrial-penetrating peptides (MPP), etc. These molecules share common properties of lipophilicity and positive charge. Through various technological modifications, they are conjugated to nanocarriers, enabling targeted drug delivery to mitochondria. Therapeutic interventions targeting mitochondria offer a hopeful direction for OA treatment. In the future, mitochondria-targeted therapy is anticipated to improve the well-being of life for the majority of OA patients. This review summarizes the link between chondrocyte mitochondrial dysfunction and OA, as well as discusses promising mitochondria-targeted therapies and potential therapeutic compounds.

Total joint arthroplasty is the optimal method for end-stage osteoarticular diseases, but aseptic loosening reduces long-term success. Our prior research demonstrated that wear particles released from loosened prostheses activate macrophages to secrete proinflammatory cytokines, thereby promoting osteoclast formation and osteolysis. Gasdermin D (GSDMD), a key regulator of pyroptosis, is a core step in the production of inflammatory factors after stimulation of macrophage pattern recognition receptors together with downstream inflammatory pathways, and histone deacetylase 6 (HDAC6)/tripartite motif-containing protein 21 (Trim21) is important in regulating activation. Yet, the specific mechanism of HDAC6/Trim21/GSDMD in wear particle–induced aseptic loosening (AL) requires further illustration. Our study will clarify the mechanism by demonstrating how HDAC6/Trim21 regulates GSDMD-associated signaling pathways in vivo and in vitro. Sterile titanium particles (TiPs) of 1.2 to 10.0 μm were co-incubated with RAW264.7 macrophages. HDAC6 selective inhibitor tubastatin A, HDAC6 overexpressing lentivirus, and Trim21 small interfering RNA were utilized to explore activation of proinflammatory pathways and polarization of macrophages was related. The mouse cranial osteolysis model was constructed to demonstrate HDAC6 regulating TiP-induced osteolysis. Macrophages were stimulated by TiPs to produce interleukin-1β as well as interferon γ, exhibiting M1 polarization. HDAC6 directedly interacted with Trim21, promoting the multiple proinflammatory responses mentioned above via GSDMD, STING pathway, and NLRP3 pathway. In vivo, HDAC6 provoked TiP-induced mice calvaria osteolysis and IL-1β production. HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway.

Talus is a critical component of the ankle joint that allows multidirectional movement essential for gait and mobility. Talus prostheses are typically used in cases of severe trauma, avascular necrosis, or end-stage arthritis. Adjacent joint arthritis is the most common complication after total talar replacement (TTR). While intervention is rarely required, varying degrees of postoperative degenerative changes have been reported in surrounding joints. Therefore, a detail evaluation of /the mechanical stability and stress distribution within talus prostheses is crucial. Recent advancements, including patient-specific implants and improved biomaterials, show promise in enhancing long-term outcomes and reducing complication rates. This study investigates the mechanical stability and stress distribution changes in a talus prosthesis after the sequential removal of surrounding ligaments and the application of varying thicknesses of cartilage overlays. Finite element analysis (FEA) was employed using CT data to create a 3D model of the talus prosthesis. The model was refined using Mimics, Geomagic, and SolidWorks, and then analyzed with Ansys. The mechanical properties of bone, prosthesis, skin, ligament, and cartilage were incorporated into the model. Various ankle positions, including neutral, dorsiflexion (5° and 10°), and plantarflexion (5°, 10°, 15°, 20°and 30°), were simulated under different ligament removal conditions. The sequential removal of surrounding ligaments, including lateral, medial, sinus tarsi, and talonavicular ligaments, did not significantly affect the stability of the talus prosthesis. Stress values ranged from 2.2257 to 3.0218 MPa, and displacement values were stable around 1.6611 to 2.2119 mm across different conditions. By comparing the effects of different cartilage thicknesses on contact area and contact stress across various flexion angles, we have the optimized the cartilage thickness, and identified a 0.5mm cartilage overlay resulted in stress distributions most similar to a normal ankle joint, enhancing the prosthesis performance. The study demonstrates that the removal of surrounding ligaments does not compromise the stability of the talus prosthesis. Importantly, a 0.5 mm cartilage overlay is optimal for achieving stress distributions comparable to a normal ankle joint. These findings offer valuable preliminary insights into stress distribution patterns following talus prosthesis implantation; however, they represent an initial step, and further experimental and clinical studies are needed to validate and extend these results. Level V, computational simulation study.

To date, monthly oral bisphosphonates have not been available in China. In this randomized, double blind, positive-controlled, multicenter phase III clinical trial, we compared the efficacy and safety of monthly minodronate versus weekly alendronate in the treatment of Chinese postmenopausal women with osteoporosis. A total of 548 participants were screened across 31 study centers, of which 330 participants were randomized into two groups: the experimental group (n = 165) received oral minodronate (50 mg/tablet once every four weeks) and alendronate placebo (once weekly), while the positive control group (n = 165) received oral alendronate (70 mg/tablet once weekly) and minodronate placebo (once every four weeks) for a duration of 48 weeks. The bone mineral density (BMD) of the lumbar spine, femoral neck and total hip were measured using dual-energy X-ray absorptiometry (DXA) at baseline and at 24 and 48 weeks. At the end of treatments, the experimental group exhibited a mean increase (SD) in BMD above the baseline at the lumbar spine, femoral neck and total hip of 4.61% (4.613%), 3.04% (4.034%) and 3.40% (3.569%), respectively, compared with those of 4.55% (3.753%), 1.86% (3.592%) and 2.30% (4.838%) in the control group. All improvements from the baseline in the two groups were statistically significant. The monthly minodronate did not cause new safety risks compared with alendronate. This study demonstrates that monthly minodronate administration is non-inferior to weekly alendronate in terms of therapeutic efficacy, while maintaining a comparable safety profile. Furthermore, the monthly dosing schedule of minodronate may significantly enhance medication adherence among osteoporosis patients, potentially improving long-term treatment outcomes.

Background:Osteoarthritis(OA)is a common degenerative joint disease character-ized by the progressive degradation of articular cartilage.Mitochondrial dysfunction and autophagy,including mitophagy,have been implicated in OA pathogenesis.Long noncoding RNAs(lncRNA)are emerging as key regulators in various cellular pro-cesses,but their roles in OA,particularly in chondrocytes,remain poorly understood.This study explores the involvement of lncRNA-GCH1 in regulating mitophagy and its impact on chondrocyte function and cartilage degradation in OA. Methods:Primary chondrocytes were isolated from the cartilage tissues of OA pa-tients and healthy controls.lncRNA-GCH1 expression was assessed using RNA-seq,reverse transcription quantitative polymerase chain reaction,and RNA fluorescence in situ hybridization.Functional assays,including Cell Counting Kit-8(CCK-8),colony formation,flow cytometry,and Western blotting,were used to evaluate the effects of lncRNA-GCH1 knockdown on chondrocyte proliferation,apoptosis,cell cycle,and mi-tophagy.Mitochondrial function was assessed by measuring adenosine triphosphate production,reactive oxygen species levels,and mitochondrial membrane potential.In vivo,a murine OA model was used to examine the impact of lncRNA-GCH1 knock-down on cartilage degradation. Results:lncRNA-GCH1 was upregulated in OA chondrocytes and localized in the cy-toplasm.Knockdown of lncRNA-GCH1 enhanced cell proliferation and arrested cell cycle in G0/G1.It also suppressed mitophagy,improved mitochondrial function,and reduced matrix-degrading enzyme expression—effects that were reversed by rapa-mycin treatment.Meanwhile,lncRNA-GCH1 knockdown reduced PTEN-induced ki-nase 1(PINK1)aggregation and in vivo local inhibition of PINK1 diminished cartilage degradation. Conclusion:lncRNA-GCH1 regulates mitophagy in OA chondrocytes,influencing mi-tochondrial function and matrix degradation.Targeting lncRNA-GCH1 may offer a potential therapeutic approach for OA treatment.

Synovial inflammation caused by osteoarthritis (OA) results in the release of numerous pro-inflammatory factors that promote cartilage degradation and pathological changes of subchondral bone. Nowadays, S100A8 has been recognized as a critical factor in the progression of inflammatory diseases, but its role in OA still needs to be confirmed. At the same time, the gene editing technology has emerged as a novel therapeutic approach for OA, such as clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) technology, but application in inflammatory gene therapy still requires advanced delivery systems to ensure cell-specific targeting and biosafety. In this study, S100A8 was confirmed as a key mediator perpetuating JAK/STAT3 pathway activation in OA progression by integrated RNA bioinformatics and synovial proteomic analyses. Based on it, we developed a polyamidoamine (PAMAM)-poly (lactic-co-glycolic acid) (PLGA) (PP) nanocore electrostatically complexed with Cas9-S100A8, encapsulated within an aptamer (apt)-grafted PLGA shell structure. This multifunctional nanocarrier could reduce dendrimer toxicity to cells and protein degradation, and enhance cellular targeting and endocytic capacity. PP-Cas9-S100A8@PLGA-apt exhibited 64.4 % S100A8 knockout efficiency (p < 0.001) and sustained mRNA release (71.5 % retention at 48 h), high cell viability (>80 %), and synovium-specific uptake (98.8 % at 0.8 μg/mL), inhibiting the JAK/STAT3 pathway. In OA-induced mice, this inhibition reduced pro-inflammatory responses, cartilage degradation, and attenuated osteophyte volume. Our findings first established PP-Cas9-S100A8@PLGA-apt as an efficient and safe Cas9 delivery tool, advancing studies of JAK/STAT3 pathway inhibition and the clinical translation of gene therapy for OA.

It was essential to identify individuals at high risk of fragility fracture and prevented them due to the significant morbidity, mortality, and economic burden associated with fragility fracture. The quantitative ultrasound (QUS) showed promise in assessing bone structure characteristics and determining the risk of fragility fracture. To evaluate the performance of a multi-channel residual network (MResNet) based on ultrasonic radiofrequency (RF) signal to discriminate fragility fractures retrospectively in postmenopausal women, and compared it with the traditional parameter of QUS, speed of sound (SOS), and bone mineral density (BMD) acquired with dual X-ray absorptiometry (DXA). Using QUS, RF signal and SOS were acquired for 246 postmenopausal women. An MResNet was utilized, based on the RF signal, to categorize individuals with an elevated risk of fragility fracture. DXA was employed to obtain BMD at the lumbar, hip, and femoral neck. The fracture history of all adult subjects was gathered. Analyzing the odds ratios (OR) and the area under the receiver operator characteristic curves (AUC) was done to evaluate the effectiveness of various methods in discriminating fragility fracture. Among the 246 postmenopausal women, 170 belonged to the non-fracture group, 50 to the vertebral group, and 26 to the non-vertebral fracture group. MResNet was competent to discriminate any fragility fracture (OR = 2.64; AUC = 0.74), Vertebral fracture (OR = 3.02; AUC = 0.77), and non-vertebral fracture (OR = 2.01; AUC = 0.69). After being modified by clinical covariates, the efficiency of MResNet was further improved to OR = 3.31–4.08, AUC = 0.81–0.83 among all fracture groups, which significantly surpassed QUS-SOS (OR = 1.32–1.36; AUC = 0.60) and DXA-BMD (OR = 1.23–2.94; AUC = 0.63–0.76). This pilot cross-sectional study demonstrates that the MResNet model based on the ultrasonic RF signal shows promising performance in discriminating fragility fractures in postmenopausal women. When incorporating clinical covariates, the efficiency of the modified MResNet is further enhanced, surpassing the performance of QUS-SOS and DXA-BMD in terms of OR and AUC. These findings highlight the potential of the MResNet as a promising approach for fracture risk assessment. Future research should focus on larger and more diverse populations to validate these results and explore its clinical applications.

Bone regeneration is a multifaceted process involving the well-coordinated interaction of cellular functions such as the regulation of inflammation, the formation of new blood vessels, and the development of bone tissue. Bone regeneration is a multifaceted process involving the well-coordinated interplay of multiple cellular activities, such as inflammation control, blood vessel and bone tissue. Zhang et al developed a multifunctional hydrogel system embedded with bone marrow stromal cell-derived exosomes to address the challenges of large bone defects. This innovative approach demonstrated the dual-role capability of bone marrow stromal cell-derived exosomes in directing cell fate by significantly enhancing both angiogenesis and osteogenic differentiation in vitro. The hydrogel system effectively promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, fostering an environment that supports bone repair. The effectiveness of this hydrogel was validated in a murine fracture model, which promoted significant bone regeneration and functional vascularization. Despite compelling evidence, this study highlights areas for further investigation, including detailed descriptions of experimental procedures, control group selection, long-term outcomes, and the evaluation of inflammation status in vivo. Addressing these limitations will enhance the robustness and impact of the findings.