Background:Osteoarthritis (OA) is a common degenerative joint disorder and there are currently no effective therapies to impede its destructive progression. Astragaloside IV (AS-IV), a natural compound, exhibits promising chondroprotective effects, yet its specific molecular mechanisms remain poorly clarified. Thus, this study employed transcriptomic profiling combined with bioinformatics analysis to identify OA-related characteristic genes, and further conducted experiments to verify the potential therapeutic mechanism of AS-IV. Methods:Analysis of the GSE114007 dataset was performed using False Discovery Rate (FDR)-adjusted p-values and quantile normalization to mitigate batch effects. Weighted gene co-expression network analysis (WGCNA) was utilized to identify key modules. Nine OA-related feature genes were identified and validated in two external datasets (GSE129147 and GSE51588) using LASSO with 10-fold cross-validation and a random forest algorithm to minimize the risk of optimistic bias. Furthermore, gene set enrichment analysis (GSEA) was conducted. The underlying mechanisms were validated through molecular docking, cellular thermal shift assay (CETSA), as well as in vitro experiments using ATDC-5 cells and in vivo assays with OA mice. Results:We identified 1548 differentially expressed genes (DEGs) primarily enriched in the extracellular matrix, with PI3K-Akt signaling closely related to OA. The MEBlack module was strongly associated with OA (cor = -0.79, p<0.0001). GSEA showed the feature genes were associated with the adipocytokine signaling pathway and glycosaminoglycan biosynthesis. Furthermore, molecular docking and CETSA indicated that ETS2 served as a potential interacting target of AS-IV. In the destabilization of the medial meniscus (DMM)-induced OA mice, the results of Safranin O/Fast Green staining confirmed that AS-IV alleviated cartilage loss and lowered OARSI scores. Mechanistically, AS-IV slowed OA progression by upregulating Col2a1 expression, suppressing MMP13 levels, and reducing inflammatory markers such as IL-1β and TNF-α. Importantly, AS-IV enhanced ETS2 expression in osteoarthritic chondrocytes. Consistently, in vitro functional assays revealed that knockdown of ETS2 in chondrogenic ATDC-5 cells partially reversed both the chondroprotective and anti-inflammatory effects of AS-IV, verifying the essential role of ETS2 in mediating the therapeutic effects of AS-IV against OA. Conclusion:Collectively, these findings point to the vital function of ETS2 in OA pathogenesis and demonstrate that AS-IV attenuates cartilage degradation and inflammatory responses by upregulating ETS2, thereby retarding OA development.

Skeletal muscle is essential for voluntary movement and exhibits a remarkable capacity for regeneration following injury. NFIX, a member of the Nuclear Factor I (NFI) family of transcription factors, plays a critical role in both skeletal muscle development and regeneration. Despite its emerging importance, the molecular basis of NFIX-mediated DNA recognition and transcriptional regulation in skeletal muscle remains poorly defined. Here, we demonstrate that NFIX promotes key cellular processes in skeletal muscle cells, as siRNA-mediated knockdown of NFIX significantly reduces cell proliferation, increases apoptosis, and impairs differentiation. Transcriptomic analysis revealed that NFIX regulates a network of genes involved in muscle metabolism, stress responses, and immune inflammatory responses. Biophysical characterization showed that NFIX exists as a monomer in solution and binds palindromic DNA with a 1:1 stoichiometry. A high-resolution crystal structure of the NFIXDBD bound to palindromic DNA reveals a monomeric binding mode driven by base-specific recognition of the TGGCA motif. Mutations that disrupt key DNA-contacting residues abolished both DNA binding and transcriptional activation in luciferase reporter assays. Together, these findings define the molecular mechanism of NFIX-dependent gene regulation in skeletal muscle and establish a structural framework for its function, providing new insights into the potential therapeutic targeting of NFIX in muscle diseases.

Metabolic disorders and osteoarthritis (OA) are chronic noncommunicable diseases with high global prevalence. Accumulating evidence underscores a strong association between metabolic illnesses and the onset and progression of the OA. This review systematically summarizes the current insights and mechanisms between metabolic disorders (obesity, hyperglycemia, dyslipidemia, hypertension, and gut microbiota dysbiosis) and OA from both epidemiology and molecular biology perspectives. Furthermore, we comprehensively elaborate on the latest therapeutic strategies for metabolic disease-related OA, emphasizing chronic inflammation and mitochondrial dysfunction as core pathophysiological bridges. Collectively, this review provides a theoretical and translational overview for the precise management of metabolic-related OA to facilitate new discoveries in chronic disease comorbidity prevention.

Study Design. Clinical retrospective study. Objective. The authors aim to analyze the relationship between paraspinal muscle degeneration and degree of L4-5 Degenerative lumbar spondylolisthesis (DLS). Summary of Background Data. While paraspinal muscle degeneration is thought to contribute to spondylolisthesis severity, this relationship has yet to be fully characterized. Methods. A retrospective analysis was performed of all neurosurgical patients admitted to the Columbia Neurosurgery Spine Division for treatment of L4-5 DLS between January 2018 and March 2024. Preoperative lumbopelvic parameters and slip percentage (SP) were calculated from standing radiographs; paraspinal muscle volume (MV), fatty volume (FV) and fatty infiltration (FI) of posterior paraspinal muscle were derived from MRI images using 3D Slicer (Earth, TX). Correlation and multiple linear regression analyses were used to assess the relationship between SP and paraspinal MV, FV, FI, and spinopelvic parameters. Results. 221 patients with average SP of 23.74±0.09% were included. The female patients had higher SP, lumbar lordosis (LL), pelvic incidence (PI) and lower IVA than the male patients. However, paraspinal MV was lower and FI was higher in the Meyerding Grade II and female groups compared to the Grade I and male groups ( P <0.01). There was a positive correlation between SP and metrics of fat replacement ( P <0.01) and a negative correlation between SP and metrics of paraspinal muscles volume ( P <0.01) at the L4-5 level. A stepwise multivariate regression ultimately included MFI, IVA, and LL and accounted for 15.2% of the variance in SP. Conclusion. In this single center retrospective study, greater degree of spondylolisthesis was modestly associated with lower MV and increased FI of the lumbar paraspinal muscles, suggesting that paraspinal muscle degeneration may be one of several important factors in the development of spondylolisthesis.

Background:Knee osteoarthritis (KOA) is the leading cause of knee joint dysfunction. Manual therapy (MT) can decrease patients' levels of pain and improve their functionality. But most traditional methods focus solely on the knee joint or its surrounding tissues, neglecting the impact of the waist, hip, ankle, and lower limb alignment on KOA. The objective is to clarify the effects of the five-step knee adjustment manipulation on KOA, evaluate its efficacy, and explore new treatment approaches for manual KOA therapy. Methods:(1) 45 healthy volunteers will be recruited to observe the differences in lower limb alignment, quadriceps cross-sectional area, knee joint range of motion (ROM), and gait between healthy individuals and KOA participants. (2) Conduct a multi-center, randomized, single-blind, controlled clinical trial. 120 eligible participants will be included and randomly assigned to a five-step knee adjustment manipulation (FS) group or a sham manipulation (SM) group with a ratio of 1:1. Each group will receive 2 sessions per week applied for 4 weeks and then be followed up for another 8 weeks. The primary outcome is visual analogue scale (VAS). The secondary outcomes include Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, ROM, quadriceps cross-sectional area (CSA), gait analysis, and so on. Conclusion:This technique emphasizes a holistic approach, addressing the lumbar spine, hip, knee, and ankle joints, as well as related muscle groups, to correct lower limb alignment and restore muscle and bone balance. We think it will contribute to providing a promising alternative intervention for middle-aged and older adults with KOA. Trial Registration:The study was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (Ethics No.: 2024SHL-KY-70-01). Registered in Chinese Clinical Trial Registry (No. ChiCTR2400085536).

STUDY DESIGN:A retrospective, cross-sectional cohort study. OBJECTIVE:This study aimed to investigate the association between paraspinal muscle parameters and single-segment degenerative lumbar spondylolisthesis (DLS). SUMMARY OF BACKGROUND DATA:The relationship between lumbar paraspinal muscle morphology and single-segment DLS remains unclear. METHODS:A retrospective review was conducted on 115 patients with L4/5 single-segment DLS and 105 subjects without DLS. Two independent investigators assessed the relative cross-sectional area and fat infiltration rate of the multifidus, erector spinae, and psoas major at L3/4, L4/5, and L5/S1 levels, comparing these measurements between the 2 groups. In addition, binary logistic regression analysis was performed with DLS as the dependent variable to analyze the relative cross-sectional area and fat infiltration rate of different paraspinal muscles. Within the DLS group, the correlation between paraspinal muscle characteristics and the anteroposterior diameter of the spinal canal was examined. RESULTS:The fat infiltration rate of multifidus, erector spinae, and psoas major was higher in the DLS group than in the control group, whereas the relative cross-sectional area of multifidus and psoas major was lower in the DLS group. Binary logistic regression analysis revealed a significant correlation between the fat infiltration rate of multifidus and psoas major and DLS. The relative cross-sectional area of multifidus and erector spinae was significantly smaller below the affected segment in the DLS group compared with the control group. A significant positive correlation was observed between the relative cross-sectional area of multifidus and erector spinae and the anteroposterior diameter of the spinal canal. CONCLUSION:There is a close association between paraspinal muscle degeneration and single-segment DLS, with an increased relative cross-sectional area of the multifidus and psoas major possibly being risk factors for single-segment DLS. The restoration or enhancement of paraspinal muscle function could potentially serve as a pivotal target for the prevention and treatment of single-segment DLS. LEVEL OF EVIDENCE:Level III.

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

Background: Both Acupuncture and electroacupuncture have demonstrated effectiveness in treating knee osteoarthritis (KOA). Variations in acupuncturists' manipulations may lead to differing therapeutic outcomes. The aim of this trial is to determine the efficacy and safety of an acupuncture technique (Zha Tiao) which is characterized by eliciting muscle twitching as an objective manifestation, combine with electroacupuncture for KOA. Methods: In this randomized, placebo-controlled, single-blind trial, 78 patients with knee osteoarthritis (KOA) classified as K-L grade II or III were randomly assigned to receive either 'Zha Tiao' electroacupuncture (ZT-EA) or regular electroacupuncture (R-EA) three times weekly for four weeks in a 1:1 ratio. Participants, outcome assessors, and statisticians keep unware of treatment group assignment. Primary outcome assessments, including the visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), range of motion (ROM), Cross-Sectional Area (CSA) of quadriceps, fastest walking time over 15 meters, Short Form 12 (SF-12), axial alignment of the lower extremity and lower limb strength, were measured at baseline, during the treatment phase (at 2 and 4 weeks), and at follow-up visits (at 8 and 12 weeks). Adverse events occurring during the trial will be recorded and analyzed. In the event of subject withdrawal from the trial, intention-to-treat analysis (ITT) will be conducted. Expected Results and Conclusion: We expect this randomized trial to evaluate the effectiveness of Zha Tiao on relieving pain and increasing ability in KOA patients. The proposed acupuncture treatment might provide an alternative option for both doctor and patient. Trial registration: China Registered Clinical Trial Registration Center (ChiCTR2400085328). Registered on Jun. 05. 2024.

To critically evaluate the effects of manual therapy (MT) on pain and functional improvement in patients with rotator cuff injury (RCI), a systematic review of all randomized controlled trials (RCTs) on MT for RCI was conducted in the following databases: PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Physiotherapy Evidence Database, Chinese National Knowledge Infrastructure, Wan-fang Data, Chinese Scientific Journal Database, and Chinese Biomedical Literature database from inception to March 28, 2023. A total of 1,110 participants from 24 eligible RCTs were included in the analysis. Compared with placebo, MT could not effectively relieve pain [standardized mean difference (SMD)=-0.25; 95% CI: -0.51 to 0.01; P=0.06], although its impact on functional improvement appears limited (SMD=0.20; 95% CI: -0.09 to 0.49; P=0.18). Combining MT with exercise had significant advantages over exercise alone, as combined therapy contributed to both pain reduction (SMD=0.36; 95% CI: 0.08 to 0.64; P=0.01) and functional enhancement (SMD=0.32; 95% CI: 0.11 to 0.52; P=0.002). Furthermore, MT combined with multimodal physiotherapy showed additional benefits in pain reduction (mean difference=1.57; 95% CI: 0.18 to 2.96; P=0.03) and functional improvement (SMD=0.77; 95% CI: 0.43 to 1.12; P<0.0001) compared with multimodal physiotherapy alone. These findings highlight the superior pain alleviation and functional improvement provided by MT when combined with exercise or physiotherapy. Consequently, MT has emerged as a pivotal component of therapeutic intervention for RCI.

Background Knee osteoarthritis (KOA) is the leading cause of knee joint dysfunction. While manual treatments are effective, most traditional methods focus solely on the knee joint or its surrounding tissues, neglecting the impact of the waist, hip, ankle, and lower limb alignment on KOA. The objective is to clarify the effects of the five-step knee adjustment manipulation on KOA, evaluate its efficacy, and explore new treatment approaches for manual KOA therapy. Methods (1) Observe the differences in lower limb alignment, quadriceps cross-sectional area, knee joint range of motion (ROM), and gait between healthy individuals and KOA participants. (2) Conduct a multi-center, randomized, single-blind, controlled clinical trial. Eligible cases will be included, with conventional knee joint massage as the control. The five-step knee adjustment manipulation will be assessed by evaluating knee joint VAS and WOMAC scores, knee joint ROM, fastest 15-meter walking time, lower limb alignment, quadriceps cross-sectional area, and gait analysis. Discussion This technique emphasizes a holistic approach, addressing the lumbar spine, hip, knee, and ankle joints, as well as related muscle groups, to correct lower limb alignment and restore muscle and bone balance. We think it will contribute to providing a promising alternative intervention for middle-aged and older adults with KOA. Trial registration: The study was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (Ethics No.: 2024SHL-KY-70-01.) China Registered Clinical Trial Registration Center (ChiCTR2400085536). Registered on Jun. 12. 2024.

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带状疱疹后神经痛为顽固性难治性神经痛,属中医络病范畴.其发病部位与络病相符,病程与络病病程相似,疼痛形式多样的发病机制与络病病机相似.络损不复为其病机关键,治疗采用三期辨证、从络论治的方法.初期为毒损络脉,予自拟清毒舒络方以清热解毒、舒络止痛;中期为络脉瘀阻,予自拟活血通络方以活血化瘀、通络止痛;晚期为络虚不复,予自拟补虚护络方以益气养阴、护络止痛.同时根据疼痛不同部位及性质选用相应的止痛药对及引经药;局部疼痛迁延难愈时,采用刺络放血以祛瘀生新、畅达络脉,提高疗效.

Purpose:Non-specific chronic neck pain (NSCNP) is an increasingly common musculoskeletal disease and an important issue in the global healthcare system. Some studies have shown that the combination of manual therapy and exercise is effective in treating NSCNP but still with several limitations. Traditional Chinese manual therapy (tuina) is a Chinese manual therapy that consists of soft tissue manipulation and spinal manipulation. This study aims to design a randomized controlled trial to assess the effect of a tuina combined with specific therapeutic neck exercise modified protocol for NSCNP patients.Patients and Methods:This is a study protocol for a randomized, participant-, assessor- and analyst-blinded controlled trial. Eighty-eight eligible NSCNP patients will be randomly allocated into tuina combined with specific therapeutic neck exercise group (TSTE group) and tuina combined with sham therapeutic neck exercise group (TS group) in a ratio of 1:1. All participants will receive 8 treatment sessions applied in 4 weeks and then be followed up for another 12 weeks. Clinical data will be collected at baseline, during treatment phase (at the 2- and 4-week) and at the 8-, 12-, 16-week follow-ups. The primary outcome is the changes in neck pain intensity (visual analogue scale). The secondary outcomes include neck disability (Neck Disability Index), cervical range of motion (ROM), neck muscle endurance, cervical muscle cross-sectional area, cervical curvature and analgesic consumption. Adverse events will be collected and recorded throughout the study.Conclusion:We will discuss whether our tuina combined with specific therapeutic neck exercise modified protocol is more effective at improving pericervical muscle endurance, ROM, cervical muscle cross-sectional area and cervical curvature than tuina alone, thereby decreases neck pain and disability in individuals with NSCNP more effectively.Trial Registration:Chinese Clinical Trials Registry, ChiCTR2300067903. Registered on 31 January 2023.

Background Rotator cuff-related shoulder pain (RCRSP) is the most common cause of shoulder disorders. In China, manipulation has been used extensively for the treatment of patients with RCRSP. However, high-quality clinical evidence to support the therapeutic effect of manipulation is still limited. Methods A multicenter, participant-, outcome assessor-, and data analyst-blinded, randomized, placebo-controlled trial will be conducted. A total of 280 participants with RCRSP will be recruited from three hospitals and randomly assigned to a five-step shoulder manipulation (FSM) group or a sham manipulation (SM) group. Each group will receive four weekly treatment sessions, with all participants performing exercises at home for 12 weeks. Assessments, namely the Constant–Murley score, visual analog scale, range of motion, and 36-Item Short Form Survey, will be made at baseline, 4, 12, 18, and 24 weeks. Adverse events during the study will also be recorded. Discussion This is a pragmatic clinical trial to evaluate the efficacy and safety of FSM in patients with RCRSP. The findings of this study will provide worthy clinical evidence for manual therapy for RCRSP. Trial registration China Registered Clinical Trial Registration Center ChiCTR2000037577. Registered on 29 August 2020.

AbstractOsteoporosis (OP) is a metabolic disease characterized by bone formation and resorption disturbances. Quanduzhong Capsule (QDZC) is a common treatment for OP in China; however, the effective components and metabolites of the drug after oral administration remain largely unknown. This study aims to identify the active components, analyze the metabolite changes, and investigate the underlying mechanism against OP. In the study, ovariectomy-induced rat OP model was established, then treated with QDZC. Alendronate sodium tablets (ASTs) were used as a reference drug. The chemical constituents of QDZC were analyzed by UPLC-QTOF-MS (ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry) and network pharmacology. The metabolomics was used to analyze differences in serum metabolites of rats in different groups [Sham, Model, Model + QDZC, and Model + AST] at 4, 8, and 12 weeks. Body weight and bone mineral density (BMD) were assessed. Enzyme-linked immunosorbent assay was used to determine serum levels of Akt, p-Akt, ERK, and p-ERK. Our data suggested 86 different chemicals from QDZC, including nine core compounds. QDZC significantly regulated 25 biomarkers linked to arachidonic acid metabolism and unsaturated fatty acid biosynthesis, and promoted serum expression of Akt, p-Akt, ERK, and p-ERK. QDZC might act by activating PI3K-Akt and MAPK signaling pathways. In addition, QDZC may use arachidonic acid derivatives to inhibit osteoclast generation and bone resorption and enhance calcitriol formation to improve calcium absorption and increase bone mass.

Osteoporosis (OP), a prevalent public health concern primarily caused by osteoclast-induced bone resorption, requires potential therapeutic interventions. Natural compounds show potential as therapeutics for postmenopausal OP. Emerging evidence from in vitro osteoclastogenesis assay suggests that aconine (AC) serves as an osteoclast differentiation regulator without causing cytotoxicity. However, the in vivo functions of AC in various OP models need clarification. To address this, we administered intraperitoneal injections of AC to ovariectomy (OVX)-induced OP mice for 8 weeks and found that AC effectively reversed the OP phenotype of OVX mice, leading to a reduction in vertebral bone loss and restoration of high bone turnover markers. Specifically, AC significantly suppressed osteoclastogenesis in vivo and in vitro by decreasing the expression of osteoclast-specific genes such as NFATc1, c-Fos, Cathepsin K, and Mmp9. Importantly, AC can regulate osteoclast ferroptosis by suppressing Gpx4 and upregulating Acsl4, which is achieved through inhibition of the phosphorylation of I-κB and p65 in the NF-κB signaling pathway. These findings suggest that AC is a potential therapeutic option for managing OP by suppressing NF-κB signaling-mediated osteoclast ferroptosis and formation.

文章总结施杞教授辨治强直性脊柱炎的临证经验,施教授认为强直性脊柱炎应从"痹"论治,重视痰、瘀、毒邪,注重调和气血.根据病情演变进程,分为急性发作期、缓解稽留期、慢性迁延期3期,治疗上以圣愈汤加柴胡为底方作为调和气血的基础方,急性发作期采用调和气血下的祛邪不伤正,缓解稽留期和慢性迁延期则主张调和气血下的扶正不留邪.

Osteoporosis (OP) is a common skeletal disease, characterized by decreased bone formation and increased bone resorption. As a novel Chinese medicine formula, Zhuanggu Busui formula (ZGBSF) has been proved to be an effective prescription for treating OP in clinic, however, the pharmacological mechanisms underlying the beneficial effects remain obscure. In this study, we explored the pharmacological mechanisms of ZGBSF against OP via network pharmacology analysis coupled with in vivo experimental validation. The results of the network pharmacology analysis showed that a total of 86 active ingredients and 164 targets of ZGBSF associated with OP were retrieved from the corresponding databases, forming an ingredient-target-disease network. The protein-protein interaction (PPI) network manifested that 22 core targets, including Caspase-3, BCL2L1, TP53, Akt1, etc , were hub targets. Moreover, functional enrichment analyses revealed that PI3K-Akt and apoptosis signalings were significantly enriched by multiple targets and served as the targets for in vivo experimental study validation. The results of animal experiments revealed that ZGBSF not only reversed the high expression of Caspase-3, Bax, Prap, and low expression of Bcl-2 in osteoblasts of the OP mouse model but also contributed to the phosphorylation of Akt1 and expression of PI3K, thereby promoting osteogenesis and ameliorating the progression of OP. In conclusion, this study systematically and intuitively illustrated that the possible pharmacological mechanisms of ZGBSF against OP through multiple ingredients, targets, and signalings, and especially the inhibition of the apoptosis and the activation of PI3K-Akt signaling.

目的:观察五步整肩手法联合肩袖功能锻炼治疗慢性肩袖损伤的疗效和安全性.方法:选取2021年1月至2021年7月就诊的慢性肩袖损伤患者30例,采用五步整肩手法(每周1次)联合肩袖功能锻炼(每周6次)治疗,连续治疗4周.观察治疗前、第4周和第8周的Constant-Murley肩关节功能评分(CMS)、疼痛视觉模拟评分(VAS)及肩关节活动度的变化.结果:与治疗前相比,治疗后患者CMS提高,VAS降低,肩关节活动度改善,差异均有统计学意义(P＜0.05).结论:五步整肩手法联合肩袖功能锻炼能显著改善慢性肩袖损伤患者肩关节疼痛与功能障碍,且操作简便,安全性高,值得临床推广应用.