Rationale: Glucocorticoid (GC)-associated osteonecrosis of the femoral head (GONFH) is an incurable orthopedic illness. Reduced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is at the core of the pathogenesis of GONFH; however, its molecular mechanism remains unclear. The study aimed to explore the pathological mechanisms of GONFH and to investigate the efficacy and mechanism of naringenin (NAR) in treating GONFH. Methods: RNA sequencing was conducted to investigate the pathogenesis of GONFH and identify the potential therapeutic mechanism of NAR. The levels of autophagy, ferroptosis, apoptosis, and osteogenesis were examined in clinical, animal, and BMSC samples. Moreover, the specific binding of NAR to ULK1 and its role in promoting ser757 phosphorylation of ULK1, leading to reduced autophagy-dependent cell death and increased osteogenic differentiation of BMSCs, were investigated using molecular dynamics simulations and systematic in vivo and in vitro experiments. Results: In clinical, animal, and BMSCs samples, autophagy, ferroptosis, and apoptosis were notably increased in the GONFH group, while osteogenesis was markedly decreased. In addition, the effects of rapamycin (RAPA, an autophagy agonist) and 3-methyladenine (3-MA, an autophagy inhibitor) were investigated to confirm that the GC-induced decrease in osteogenic differentiation of BMSCs is mediated through autophagy-dependent cell death. Additionally, NAR exhibits high affinity for ULK1, which increases its inhibitory phosphorylation at ser757. This particular communication inhibits GC-induced autophagy and subsequent cell death, thereby normalizing osteogenic differentiation of BMSCs. It is interesting to note that the protective effects of NAR were abolished by pharmacological (RAPA) and genetic (ULK1-S757A mutation) interventions. Conclusions: Taken together, our work elucidates a pathogenic process involving autophagy-dependent cell death and defines NAR as a specific treatment that regulates ULK1 to halt this pathogenic cascade.

Effective disease-modifying therapies for knee osteoarthritis (KOA) remain elusive. This study developed BWTS-N@Gel, a novel composite comprising supramolecular self-assembled nanoparticles (BWTS-N) derived from the traditional Chinese medicine formula Bawei Tiaosui Decoction, encapsulated within a cross-linked hyaluronic acid hydrogel. BWTS-N features a small particle size facilitating efficient chondrocyte endocytosis, while the hydrogel matrix ensures sustained drug release, and the incorporation of BWTS-N further enhances lubrication, aligning with the "SCALE" therapeutic strategy (Safety, Cartilage protection, Anti-inflammatory, Lubrication, Efficacy). In vivo and in vitro experiments, along with ex vivo human cartilage explant studies, demonstrated that BWTS-N@Gel significantly attenuated KOA progression by suppressing chondrocyte ferroptosis. Mechanistically, the treatment preserved the GCLM/GPX4 axis, thereby enhancing glutathione synthesis, mitigating lipid peroxidation, and preventing iron-mediated cell death. These findings position BWTS-N@Gel as a promising therapeutic candidate that synergizes traditional medicine efficacy with advanced nanotechnology for targeted cartilage protection and joint lubrication in KOA management.

Aims: Patellar luxation can cause abnormal mechanical loading and is a leading cause of patellofemoral joint damage, however its contribution to femoral-tibial joint damage is poorly elucidated. In this study, we sought to investigate the role of patellar luxation in the femoral-tibial joint in both mice and humans. Methods: In this study, we generated a patellar luxation mouse model based on the standard operating procedure of destabilization of the medial meniscus (DMM) surgery which mimics osteoarthritis (OA). Then phenotypes including gait analysis, osteophyte formation, aberrant subchondral bone remodelling, cartilage degeneration, and synovitis of femoral-tibial joint were evaluated in vivo at eight weeks after surgery. Additionally, we also performed a retrospective study to investigate femoral-tibial joint characteristics in 18 patients with post-traumatic OA or recurrent patellar luxation. Results: We found that patellar luxation caused abnormal gait and augmented osteophyte outgrowth around the tibial plateau and patella. Furthermore, micro-CT analysis showed that mice treated with patellar luxation operation exhibited aberrant subchondral bone remodelling. Intriguingly, according to Safranin-O/Fast Green staining, mice with patellar luxation showed better articular cartilage integrity and less cartilage proteoglycan damage in the medial compartment of the femoral-tibial joint. Moreover, either patellar luxation operation or DMM surgery promoted the expression of TNF-α and F4/80 in synovium tissue. However, mice subjected to patellar luxation exhibited aggressive cartilage erosion in the lateral compartment of the knee joint. In addition, the clinical study showed that patellar luxation was associated with lateral cartilage degeneration of the femoral-tibial joint. Conclusion: This study confirmed that lateral patellar luxation induced subchondral bone osteopenia, promoted osteophyte formation as well as synovial inflammation, and caused lateral cartilage rather than medial cartilage degeneration in the femoral-tibial joint. Cite this article: Bone Joint Res 2026;15(4):363–374.

Osteoporosis (OP) is a prevalent skeletal disorder characterized by progressive bone mass loss and deteriorated microarchitecture, in which oxidative stress-induced mesenchymal stem cell (MSC) dysfunction serves as a core pathogenic mechanism. Yougui Pills (YGPs), a classical traditional Chinese medicine formula, are widely applied in clinical OP management, yet the cellular and molecular mechanisms underlying their anti-osteoporotic effects remain incompletely defined. This study aimed to elucidate the bone-protective role of YGPs in OP and explore the underlying mechanism, focusing on oxidative stress modulation in MSCs and the Nrf2/HO-1 signalling pathway. The bioactive components of YGPs and YGP-containing serum were characterized via UPLC. In vivo, an ovariectomy (OVX) mouse model was established to evaluate YGPs' effects on bone mass, trabecular microstructure and osteogenesis using micro-CT, histological and immunohistochemical assays; public GEO datasets were re-analysed to profile transcriptomic alterations and oxidative stress signatures in OP-derived MSCs. In vitro, H2O2 was used to induce ROS accumulation and oxidative injury in MSCs, with assessments of cell proliferation, apoptosis, ROS levels, migration and osteogenic differentiation. Network pharmacology and siRNA-mediated gene silencing were conducted for target prediction and mechanistic validation. In vivo results showed that YGP treatment significantly ameliorated OVX-induced osteopenia, increased bone mineral density, improved trabecular microstructure, and upregulated osteogenic markers (ALP, OCN, Runx2, COL1A1). Transcriptomic re-analysis revealed upregulated oxidative stress markers in OP MSCs, consistent with In vitro findings that YGPs attenuated H2O2-triggered ROS overproduction, suppressed apoptosis and ectopic lipid deposition, and enhanced MSC proliferation, migration and osteogenic differentiation. Mechanistically, YGPs activated the Nrf2/HO-1 signalling axis, while Nrf2 knockdown abrogated YGPs' cytoprotective and pro-osteogenic effects. In conclusion, YGPs mitigate oxidative stress-induced MSC dysfunction and promote osteogenesis via the Nrf2/HO-1 pathway, supporting YGPs as a promising therapeutic candidate for OP.

Low back pain (LBP) is a widespread global health concern that profoundly impairs patients’ quality of life and productivity. Intervertebral disc degeneration (IVDD) is considered a major pathological factor in low back pain, yet the underlying mechanisms of IVDD remain incompletely understood. Current treatment strategies primarily focus on symptomatic relief through medication or surgical removal of degenerated tissue, lacking effective interventions that can reverse the degenerative process. This study investigates the role of fatty acid metabolism in IVDD and proposes a novel therapeutic strategy. Through single-cell sequencing and multi-omics analysis of clinical samples, we identified ACOT13 as a key regulator of fatty acid metabolism. We demonstrated that under pathological conditions, ACOT13 inhibits the AMPK/ACC signaling pathway, leading to disrupted fatty acid metabolism, mitochondrial dysfunction, and subsequently, pyroptosis, which accelerates IVDD progression. Furthermore, we developed an innovative self-assembled nanoparticles based on a traditional Chinese medicine formula. Employing molecular dynamics simulations, we elucidate the self-assembly mechanism, identifying the core constituents and establishing the key roles of hydrophobic interactions, π-π stacking, and hydrogen bonding as the driving forces. Moreover, we revealed that this nano-formulation suppresses ACOT13 function, activates the AMPK/ACC pathway, and improves fatty acid metabolism and mitochondrial function, thereby suppressing pyroptosis and ultimately alleviating IVDD progression. In summary, this study explores a novel mechanism of IVDD from the perspective of fatty acid metabolism and identifies key active components (N-QJZG) from a traditional Chinese medicine decoction, providing new insights for IVDD treatment and promoting the modernization of traditional Chinese medicine research.

Knee osteoarthritis (KOA) is frequently accompanied by periarticular muscle atrophy. Targeting muscle atrophy holds promise for delaying KOA progression; however, therapeutic strategies that simultaneously protect both muscle and joint remain scarce. The traditional Chinese formula Danggui Buxue Decoction (DBD) shows potential in attenuating KOA-associated muscle atrophy, yet its clinical application is hindered by poor stability, low bioavailability, and insufficient tissue targeting. Plant-derived extracellular vesicles (EVs), as natural nanocarriers, can effectively overcome these limitations, and fresh herbs retain higher levels of bioactive constituents than their dried counterparts. In this study, we integrated traditional formula compatibility, fresh herb extraction, and EV isolation techniques to prepare nanovesicles from fresh Astragalus membranaceus and Angelica sinensis, and combined them at the 5:1 ratio of DBD to obtain Astragalus-Angelica sinensis-Derived Extracellular Vesicles (AA‑EVs). AA‑EVs were then characterized by TEM, zeta potential analysis, nanoparticle tracking analysis, and LC‑MS. In an anterior cruciate ligament transection (ACLT)-induced mouse model of KOA with periarticular muscle atrophy, oral administration of AA‑EVs dose‑dependently ameliorated muscle atrophy, restored muscle mass and motor function, and delayed KOA progression, with overall therapeutic efficacy significantly superior to that of DBD decoction. In the TNF‑α‑stimulated C2C12 myotube atrophy model, AA‑EVs inhibited myotube diameter reduction, restored the expression of myogenic regulatory factors MyoD and MyoG, suppressed the atrophy‑related ubiquitin ligases Murf‑1 and Atrogin‑1, and reduced lipid droplet accumulation as well as MDA and free fatty acid levels. Integrated transcriptomic and metabolomic analyses identified PPARγ signaling and fatty acid metabolism as the core pathways of AA-EVs effect on KOA. Mechanistically, AA‑EVs upregulated PPARγ and fatty acid oxidation‑related gene expression; siRNA‑mediated knockdown of PPARγ abolished the protective effects of AA‑EVs on myotube morphology, lipid accumulation, and myogenesis‑related gene expression. This study confirms that AA‑EVs alleviate periarticular muscle atrophy and delay KOA progression through PPARγ‑mediated fatty acid metabolism, providing a new strategy for the treatment of KOA and periarticular muscle atrophy.

Osteoarthritis (OA), a prevalent degenerative joint disease, currently lacks effective therapies. Self-assembled nanomedicines derived from herbs create innovative pharmaceutical formulations, and offer promising therapeutic strategies for OA treatment. Considering the treatment of Shen-Sui-An-Kang (SSAK) decoction in clinical OA symptoms, here we isolated the nanoparticles from SSAK decoction, and then investigated their effects on OA treatment. By using gradient centrifugation and dialysis, self-assembled nanoparticles of SSAK (N-SSAK) were isolated based on the hydrophobic interactions, hydrogen bonding, and π-π stacking. After determining the physical characteristics of N-SSAK, we investigated the therapeutic effect of N-SSAK in vivo and in vitro, and found that they alleviated cartilage degeneration, maintained the homeostasis of cartilage matrix, and reduced pain sensitivity. Mechanistically, we demonstrated that N-SSAK exerted their effects by modulating retinol metabolism and inhibiting lipid peroxidation in OA chondrocytes. To improve the sustained release and targeted delivery of N-SSAK, we developed an injectable hydrogel-based delivery system (HA-MIX@N-SSAK). Compared to N-SSAK oral administration, HA-MIX@N-SSAK showed better efficacy on cartilage protection and slowing OA progression. Overall, our findings indicate that N-SSAK suppress the progression of OA by regulating retinol metabolism and inhibiting chondrocyte ferroptosis, implying that HA-MIX@N-SSAK may be a novel strategy for clinical OA treatment.

Background/objective Cartilage defects (CDs) present a significant challenge in orthopaedic medicine. Owing to the inherently limited regenerative capacity of cartilaginous tissue, defects usually do not heal via natural repair processes. Consequently, damaged tissue is replaced by fibrocartilage-like tissues instead of the original hyaline cartilage. Therefore, inhibiting fibrocartilage formation while promoting hyalinisation may represent a novel strategy for CD therapy. Although studies have explored the role of interleukin (IL)-17A and ferroptosis in the fibrosis of visceral organs, such as the liver, lungs, and kidneys, their implication in cartilage fibrosis and fibrocartilage formation remains unclear. Herein, we aimed to determine whether IL-17A and ferroptosis are collectively involved in the process of cartilage fibrosis and to investigate the effects of amygdalin (AMD) and magnesium ions (Mg2+) in cartilage regeneration and the potential molecular mechanisms underlying these effects. Methods Cartilage samples were collected from patients with osteoarthritis and subjected to immunohistochemistry analysis to assess fibrocartilage formation indicators within the degenerated areas. Quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry analyses were employed to assess changes in cartilage anabolism and expression of fibrocartilage markers after treatment with different concentrations of AMD. We also treated chondrocytes with an IL-17A/RA antagonist, a ferroptosis inhibitor, a ferroptosis inducer, and AMD, and measured the changes in fibrocartilage-, ferroptosis-, and IL-17 signalling-associated factors. Finally, mice with microfracture (MF)-induced CDs were administered intra-articular injections of either saline, AMD (10 μmol/L), MgCl2 (0.5 mmol/L), or AMD (10 μmol/mL) plus MgCl2 (0.5 mmol/L) twice a week. After 4 and 8 weeks, chondral repair was assessed through histological and immunohistochemical analyses in each group. Results IL-17A activated lipid peroxidation, leading to chondrocyte ferroptosis, while AMD suppressed IL-17 signalling, thereby mitigating the decrease in glutathione peroxidase 4 (GPX4) expression induced by IL-17A or erastin. In mice with MF surgery-induced CD, the combination of AMD and Mg2+ mitigated oxidative stress, thereby enhancing the positive effects of Mg2+. This combination led to a significant improvement in chondrogenesis, activation of anabolic processes, and reduction of catabolic activity in the articular cartilage, ultimately supporting cartilage repair and regeneration. Conclusions AMD targets IL-17 signalling to inhibit chondrocyte ferroptosis. Furthermore, the combination of AMD and Mg2+ suppresses IL-17A/GPX4 signalling, suppressing fibrocartilage formation and fostering hyaline cartilage regeneration. The translational potential of this article In the present study, we showed that IL-17A may represent a promising therapeutic target for cartilage repair and regeneration. A conservative therapeutic strategy involving joint injections of AMD (a natural plant extract) and Mg2+ (a crucial endogenous factor that promotes chondrogenesis) facilitated effective cartilage repair and regeneration. This strategy represents a cost-effective approach with potential for clinical application.

Osteoarthritis (OA) is a common degenerative disease caused by multiple pathological mechanisms wherein subchondral bone malfunction plays a substantial role. Recently, subchondral (SC) injection of orthobiologics has been attracting growing interest albeit the mainstream delivery method of mesenchymal stem cells (MSCs) is through intra-articular (IA). This study investigates the effect of SC injection of human umbilical cord mesenchymal stem cells (UCMSCs) on OA and its possible therapeutic mechanism compared to IA injection. Male Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) received saline or UCMSC injections via SC or IA. Consecutive injections once a week for three weeks and withdrawal for another four weeks, followed by Radiographical scanning, histopathological, immunohistochemical, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining. Cell counting Kit-8 (CCK-8) assay, alkaline phosphatase (ALP), alizarin red staining (ARS), TUNEL, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed in TNFα-induced MC3T3-E1 cells to illustrate the exact pathogenesis mechanism. IA and SC UCMSC injections preserved cartilage, synovium, and subchondral bone parameters like trabecular bone volume fraction (BV/TV). SC injection uniquely improved Trabecular separation (Tb.Sp) and Trabecular number (Tb.N). SC and IA injections of UCMSCs demonstrated equivalent efficacy in promoting osteoblastic bone formation and attenuating aberrant angiogenesis of subchondral bone. In addition, we demonstrated that osteoblast apoptosis and Smad2-dependent TGF-beta (TGF-β) are crucial and interactive subchondral bone pathological features in OA. In vivo and vitro studies further revealed that UCMSCs inhibited excessive TGF-β/pSmad2 signaling to regulate aberrant vascularization, osteoblast apoptosis and differentiation imbalance, ultimately maintaining osteochondral homeostasis. The efficacy of UCMSCs for treating OA rats via SC injection was equivalent to that of IA; and even superior to IA in terms of subchondral bone phenotype via regulating apoptosis and TGF-β/pSmad2 signaling in osteoblasts, suggesting SC injection of UCMSCs as a potential and promising cell therapy for OA treatment.

The study aimed to explore the efficacy and potential mechanisms of a naturally aromatic cyanogenic compound-amygdalin (AMY) in treating glucocorticoid (GC)-associated necrosis of the femoral head (GANFH). We demonstrated that GC exacerbates the oxidative stress (OS) microenvironment via promoting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression in human, rat, and mesenchymal stem cells (MSCs) samples, thus generating excessive reactive oxygen species (ROS), leading to increased apoptosis and unbalanced osteolipogenic differentiation. Furthermore, computational docking results revealed that AMY could bind specifically to the predicted binding sites of NOX4. Additionally, AMY ameliorated the OS microenvironment of MSCs via decreasing NOX4 expression and inhibiting NOX4/ROS/p38MAPK signaling, thereby reversing the GC-induced apoptosis and imbalanced osteolipogenic differentiation, and ultimately alleviating GANFH. In summary, we demonstrated for the first time that AMY attenuated apoptosis and maintained osteolipogenic differentiation balance in MSCs via specifically targeting NOX4, inhibiting NOX4/ROS/p38MAPK signaling, thereby treating GANFH.

Background:Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune system dysregulation and the production of autoantibodies, leading to widespread inflammation and multi-organ damage. Despite clinical observations have shown that approximately 1.4-68.7% of SLE patients develop vertebral osteoporosis (OP), the underlying mechanisms remain poorly defined. This study utilized the MRL/lpr mouse model, which effectively replicates human SLE manifestations, to investigate the impact of SLE on vertebral bone homeostasis. Methods:Female MRL/lpr mice were employed to investigate SLE-induced bone loss. The study comprehensively evaluated bone structural changes through micro-CT analysis, histological assessment, and bone metabolic markers. Specifically, we analyzed trabecular parameters (TV, BV, BV/TV, Tb.Th), inflammatory cytokine profiles (TNF-α, IL-6, IL-1β, IL-18), osteogenic markers (RUNX2, OSTERIX, ALP, OPG), osteoclastogenic indicators (TRAP, RANKL, CTSK), and ferroptosis-related proteins (FACL4, FTH1, GPX4). Results:SLE progression in MRL/lpr mice led to significant vertebral bone loss and OP phenotype, evidenced by reduced bone volume fraction (BV/TV) and trabecular thickness (Tb.Th). The inflammatory microenvironment was characterized by elevated TNF-α and IL-6 levels, which disrupted bone homeostasis by suppressing RUNX2, OSTERIX, and OPG expression while enhancing RANKL signaling. Mechanistically, SLE induced ferroptosis through increased FACL4 and FTH1 expression coupled with decreased GPX4 levels, leading to impaired osteoblast function and enhanced osteoclast activity. Conclusion:SLE-associated vertebral OP is mediated by inflammation-driven ferroptosis, disrupting the balance between bone formation and resorption, offering novel insights into potential therapeutic strategies for managing bone loss in SLE patients.

Abnormal accumulation of both intracellular and extracellular free nucleic acids drives chronic inflammation in intervertebral disc degeneration (IVDD). Despite the development of numerous minimally invasive treatments for IVDD, systematic approaches targeting the chronic inflammation mediated by both nucleic acid types are lacking. We propose a dual clearance strategy that inhibits mitochondrial DNA release inside nucleus pulposus cells while removing extracellular DNA from the disc microenvironment. Using single-cell sequencing and clinical samples, we revealed how both nucleic acid types drive inflammation. We then developed a targeted nanovesicle system delivering a mitochondrial membrane-stabilizing small molecule to block DNA leakage and inflammatory signaling, along with a hydrogel that captures extracellular DNA to prevent immune activation. In a rat model, this approach significantly slowed disease progression. This targeted dual nucleic acid clearance strategy provides a approach for treating IVDD and offers a theoretical framework for addressing other nucleic acid-related inflammatory diseases.

Atrazine (ATZ), a frequently used herbicide, has well-documented toxicities in various organisms, yet its specific impact on skeletal muscle remains largely uncharted. Here, we found that ATZ inhibited myotube formation in C2C12 myoblasts and decreased both body weight and the cross-sectional areas of type IIA, IIB, and IIX myofibers in mice. Furthermore, ATZ drove muscle fiber shifting from mixed oxidative/glycolytic type IIA to fast-glycolytic type IIB, reduced satellite stem cell abundance, and contributed to excessive lipid accumulation. Mechanistically, transcriptomic analyses indicated that ATZ triggered inflammation, oxidative stress, adipogenesis, and protein degradation, as evidenced by elevated ROS, augmented NF-κB pathway, and disrupted protein homeostasis. By integrating transcriptomic data with eQTL and grip strength GWAS findings from 454,473 individuals, and applying Mendelian randomization and Bayesian colocalization analyses, we pinpointed 14 genes that were both dysregulated by ATZ and causally linked to muscular strength. Further interrogation of single-cell/nucleus RNA-sequencing data revealed cell type-specific patterns of 10 reasonable causal genes (Jund, Limd2, Ppm1j, Procr, Cdo1, Irs1, Kif1b, Nav1, Nexn, Peak1), highlighting the multifaceted cellular processes underlying ATZ-inflicted muscle damage. Notably, Morroniside, with anti-inflammatory and antioxidant properties, rescued several potential therapeutic targets (Limd2, Jund, Irs1, Kif1b, Peak1, Nav1) and C2C12 myotubes from ATZ-induced atrophy. Collectively, our study sheds light on the effects and molecular underpinnings of ATZ-mediated skeletal muscle toxicity and brings forward viable therapeutic targets and strategy. The multi-omics approach offers a robust framework for translating findings from cell/animal models to human relevance in toxicological research.

OBJECTIVE:To explore the epidemiological characteristics of knee osteoarthritis (KOA) among the elderly in the community, and its correlation with bone mass loss. METHODS:A cross-sectional study was conducted on elderly community population over 50 year old from 12 community health service centers in Zhejiang province. Their gender, age, body mass index (BMI), T value and KOA diagnosis were collected using face to face questionnaire survey. Univariate regression was used to analyze the influence of age, gender, BMI and bone loss on KOA. Logistic multivariate regression model was used to analyze the independent effect of bone mass loss on KOA. RESULTS:Among 4 173 subjects in this study, 1 710 of them were had a KOA. The prevalence rate was 40.9%. The mean age, the proportion of females and the mean BMI in KOA patients were (65.5±3.8) years old, 67.7%(1 158/1 710) and(24.59±1.28) kg·m-2, respectively, which were significantly higher than (58.5±3.2) years old, 51.3%(1 263/2 463), and (23.48±1.25) kg·m-2 in non-KOA subjects (P<0.001). In the population aged from 60 to 69 years old, the influence of osteopenia and osteoporosis on the prevalence of KOA was[OR=1.21, 95%CI(1.00, 1.46), P=0.053 2], [OR=1.42, 95%CI(1.14, 1.78), P=0.002 2]. The influence of male and female osteoporosis on the prevalence of KOA was [OR=1.52, 95%CI(1.16, 1.99), P=0.002 7] and [OR=1.87, 95%CI(1.51, 2.32), P<0.000 1], respectively. In the population of 24 kg·m-2≤BMI<28 kg·m-2, the influence of osteopenia and osteoporosis on the prevalence of KOA was [OR=1.47, 95%CI(1.21, 1.80), P=0.000 1], [OR=2.69, 95%CI(2.11, 3.42), P<0.000 1], respectively. After controlling the confounding factors of age, gender and BMI, compared with people with normal bone mass, the effect of osteopenia on the prevalence of KOA was [OR=1.34, 95%CI(1.08, 1.67), P=0.009 2], and the effect of osteoporosis on the prevalence of KOA was [OR=1.38, 95%CI(1.06, 1.79), P=0.017 9]. CONCLUSION:Elderly overweight women are more likely to develop KOA. Bone mass loss is an independent risk factor for KOA, which will significantly increase the prevalence of KOA in people overweight or aged 60 to 69 years old.

Sarcopenia, a progressive and systemic skeletal muscle disorder marked by the accelerated deterioration of both muscle function and mass, is highly prevalent among the elderly population, significantly contributing to an elevated risk of adverse outcomes, including falls, fractures, and muscle weakness. Clinical investigations have identified a strong correlation between sarcopenia and several prevalent degenerative skeletal muscle disorders. This correlation is attributed to imbalances in joint mechanics resulting from localized muscle atrophy and the influence of musculoskeletal secretory factors. In this review, we discuss the broader implications of sarcopenia and critically evaluate the currently established assessment methods. Furthermore, the clinical significance of prevalent musculoskeletal disorders (including osteoporosis, osteoarthritis, and spinal pathologies) in relation to sarcopenia, alongside the underlying mechanisms influencing this relationship, is summarized. Additionally, the effects of sarcopenia on the therapeutic efficacy of medications and surgical interventions for musculoskeletal conditions are reviewed. Sarcopenia is intricately linked to the onset, progression, and prognosis of musculoskeletal disorders. Future research should prioritize elucidating the potential mechanisms that connect muscle loss with skeletal muscle diseases, and investigating whether mitigating sarcopenia symptoms could decelerate the progression of these disorders, thereby paving new pathways for therapeutic interventions.

Background:Joint bleeding (hemarthrosis) is a major manifestation of joint trauma, especially repeated and spontaneous in hemophilia patients. Hemarthrosis has been identified to induce the excessive reactive oxygen species (ROS) accumulation and permanent damage in articular cartilage. Dihydroartemisinin (DHA), a well-known clinical anti-malaria drug with few sides effects therapy, has been reported to possess anti-oxidative activity. This study was aimed at exploring the effect of DHA on blood-induced cartilage erosion and its underlying mechanisms. Methods:Two distinct hemarthrosis models were constructed respectively by fresh blood joint injection in WT and joint needle puncture in F8 -/- mice, and then treated with DHA (10 or 20 mg/kg/day) for 4 weeks. In vitro chondrocytes treated with frozen-thaw blood and DHA (1, 5 or 10 μM) for 24 h. Histopathological, immunofluorescence and western blotting were investigated to demonstrate the effects of DHA on blood-induced chondrocyte senescence, ROS accumulation and extracellular matrix (ECM) degradation. Additionally, Nrf2 inhibitor (MLB385, 30 mg/kg for once a four days) and Nrf2-siRNA were used to investigate the relationship between DHA and Nrf2/Keap1 signaling in vitro and in vivo, respectively. Results:DHA remarkably ameliorated the cartilage degeneration in both two hemarthrosis models. Similarly, in vitro experiments confirmed that DHA promoted the synthesis of ECM in blood-stimulated chondrocytes with a dose-dependent manner. DHA also effectively suppressed blood-induced chondrocyte senescence and ROS accumulation. Mechanistically, DHA activated the Nrf2 signaling by accelerating Keap1 ubiquitination and degradation. Furthermore, Nrf2 siRNA and antagonist abolished the anti-senescence and anti-oxidative functions of DHA, resulting the severe cartilage degeneration in bleeding joint of F8 -/- mice. Conclusion:Our findings indicate that DHA effectively reduces chondrocyte senescence and mitigates cartilage destruction following hemarthrosis via activation of Nrf2/Keap1 signaling pathway. The Translational potential of this article:On the one hand, this study highlights the important role of chondrocyte senescence in hemarthrosis-induced cartilage degradation, implying that inhibiting chondrocyte senescence may be a viable therapeutic strategy for blood-induced arthropathy. On the other hand, our findings demonstrate the remarkable chondroprotective effect of DHA in bleeding joint by modulating the Nrf2/Keap1 anti-oxidative signaling pathway, suggesting DHA may serve as a potential candidate drug for the therapy of blood-induced arthropathy.

Purpose:Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse clinical manifestations, including joint symptoms. Arthritis represents one of the earliest manifestations of SLE, profoundly affecting the quality of life for affected individuals, yet the underlying mechanisms of SLE-associated arthritis remain insufficiently investigated. The study aimed to investigate the impact of SLE exacerbation on arthritis using the MRL/lpr mouse model, which closely mimics human SLE manifestations. Methods:In the present study, we evaluated the impact of SLE onset on knee joint degeneration by comparing arthritic phenotype and complex molecular alterations between 6 female 14-week-old MRL/lpr mice, which manifest SLE, and MRL/MpJ mice, which remain unaffected. Results:Our results demonstrated that MRL/lpr mice exhibited a more severe arthritic phenotype compared to MRL/MpJ mice, characterized by elevated Osteoarthritis Research Society International (OARSI) scores (P < 0.01), disrupted extracellular matrix metabolism, impaired chondrocyte proliferation and increased apoptosis. Notably, inflammatory cytokines proteins such as IL-1β and TNF-α (both P < 0.01), IL-18 and IL-6 (both P < 0.05), were significantly increased in articular cartilage of MRL/lpr mice, accompanied by increased expression of calcitonin gene-related peptide (CGRP) (P < 0.05), NETRIN-1, and NESTIN (both P < 0.01), indicating that SLE promotes inflammation response and sensory nerve ingrowth in the knee joint, contributing to the progression of arthritis. Mechanistic analysis revealed that SLE exacerbation intensified chondrocyte pyroptosis by upregulating pyroptotic-related proteins, including NLRP3, CASPASE-1, and gasdermin D (all P < 0.01), through the regulation of the nuclear factor erythroid 2-related factor (NRF-2)/KEAP-1 and nuclear factor kappa-B (NF-κB) pathway. Conclusion:Collectively, our findings underscore the mechanistic connection between chondrocyte pyroptosis and arthritis exacerbation in SLE, suggesting potential therapeutic targets for mitigating arthritis progression in the context of SLE.

Synovitis is a key factor in temporomandibular joint osteoarthritis (TMJOA) and could be an early sign of the disease. Notably, synovitis and its macrophage component represent a target of interest for developing treatments. Dental pulp stem cells (DPSCs) are derived from the neural crest, coincidentally with maxillofacial tissues, thus attracting significant interest in situ maxillofacial regenerative medicine. However, there is a relative scarcity of studies investigating the role of DPSCs in the temporomandibular joint (TMJ) synovial macrophage. This study aimed to evaluate the regulatory and reparative capabilities of DPSCs on synovitis in TMJOA rat models and to elucidate their specific mechanisms of action on synovial macrophages. In vivo, three groups were established: the control group, which had neither induction nor treatment; the OA group, consisting of rats with OA but without any treatment; and the DPSCs treatment group, where rats with OA received DPSCs therapy. Progressive TMJOA was induced in rats via intra-articular injection of complete Freund’s adjuvant and sodium iodoacetate. After 2 weeks, DPSCs were injected into the joint cavity as a therapeutic intervention. Meanwhile, normal saline was injected into the joints of rats in both the control and OA groups. Four weeks after treatment, histological analysis was performed to evaluate the repair of synovitis. In addition, an in vitro co-culture system, consisting of macrophages and DPSCs. Each group was assessed using techniques, including mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, and Western blot analysis. Furthermore, apoptotic primary neutrophils were co-cultured with polarized macrophages to observe the phagocytic ability of macrophages towards apoptotic primary neutrophils under different treatments in vitro. In the rat model, compared with the OA group, the DPSCs group exhibited reduced cell infiltration and collagen deposition, along with elevated levels of anti-inflammatory CD206 and decreased levels of inflammatory CD86, and enhanced the ability of macrophages to phagocytize apoptotic cells in vivo and in vitro. Notably, DPSCs exhibited enhanced efficacy in upregulating autophagosome expression, promoting co-localization with mitochondria and lysosomes, and modulating the expression of mitochondrial mitophagy proteins. Furthermore, inhibition of mitophagy in M1 macrophages partially attenuated the M2 polarization effect and phagocytosis induced by DPSCs. DPSCs significantly mitigate synovitis in TMJOA rats by enhancing M2 polarization and efferocytic functions of macrophages. This study underscores the potential of DPSCs as a therapeutic strategy for TMJOA by modulating synovial macrophage functions through the regulation of mitophagy.

[This corrects the article DOI: 10.1016/j.bioactmat.2024.05.039.].